13. SMAD4 p.I500V FrequencyΒΆ

The example variant we will be evaluating using the ACMG guidelines is a missense mutation in the SMAD4 gene. You will see red notifications across the top interface of VSClinical, which indicate that there are critical criteria to evaluate. The first tab we will investigate will be the frequency of this mutation in the Population tab. Navigate to the Population tab by selecting it.

population tab

Figure 13-1: Population tab.

In the Population tab you can then expand the dropdowns including Tolerated Frequency, gnomAD Exomes Frequency and 1000 Genomes Frequency. The Tolerate Frequency will display the Gene/Disorder Inheritance model as well as the threshold frequencies implemented in gnomAD and 1000 Genomes. For this SMAD4 gene the inheritance model is identified as Dominant. It is also worth mentioning that as of the 2015 publication on the original ACMG Guidelines, the default frequency threshold for BA1 is 5% but Golden Helix implemented the more clinically accepted 1% threshold. These details are integrated into the documentation for the criteria, which can be accessed by selecting See further discussion on PM2 in the Show Details section for BA1.

population tab

Figure 13-2: Tolerated frequency.

Next, we can investigate the frequency in gnomAD and 1000 Genomes and both databases will display the highest frequency among individual subpopulations. Although this variant is observed in 1 of 113,754 (0.0009%) individuals in European (Non-Finnish) populations according to gnomAD, it is considered novel in 1000 Genomes. With a low or absent frequency in the population catalogs, we can answer the YES to the first relevant scoring criteria PM2, which states if the variant is: Absent from controls in population catalogs. Notice once yes has been selected, it will add it to the ACMG Scoring model on the right side.


Figure 13-3: ACMG criteria PM2.