ClinVar Genomic variation as it relates to human health

Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as Benign. Following criteria are met: 0107 - This gene is known to be associated with autosomal dominant disease. 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein. 0308 - Population frequency for this variant is out of keeping with known disease incidence. 0405 - Variant is located in a gene associated with a severe early onset condition that is TOLERANT to loss-of-function variation. 0507 - Identified variant type is not compatible with in-silico predictions of pathogenicity. 0706 - Variant impact is not consistent with known spectrum of pathogenic variants in the affected gene. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

FAM111A: BS1, BS2

The FAM111A p.Phe264Leufs*7 variant was not identified in the literature but was identified in dbSNP (ID: rs533676902) and ClinVar (classified as benign by Invitae). The variant was identified in control databases in 1502 of 282234 chromosomes (8 homozygous) at a frequency of 0.005322 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 1155 of 128682 chromosomes (freq: 0.008976), European (Finnish) in 196 of 25106 chromosomes (freq: 0.007807), Other in 27 of 7208 chromosomes (freq: 0.003746), South Asian in 65 of 30600 chromosomes (freq: 0.002124), Latino in 40 of 35400 chromosomes (freq: 0.00113), African in 18 of 24936 chromosomes (freq: 0.000722) and Ashkenazi Jewish in 1 of 10354 chromosomes (freq: 0.000097), but was not observed in the East Asian population. This is greater than expected for the rare, autosomal dominant conditions Gracile bone dysplasia and Kenny-Caffey syndrome type 2 associated with FAM111A variants. The c.782_791dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 261 and leads to a premature stop codon 7 amino acids downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. There is currently a lack of evidence for a disease association from loss of function variants of the FAM111A gene. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).