ClinVar Genomic variation as it relates to human health

This variant is associated with the following publications: (PMID: 27267386, 28220018, 29074612, 22720333, 27253664, 27535533, 27153395, 20506337, 24423289, 17360484)

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

AIP: BS1

The AIP p.A299V variant was identified in 1 of 72 proband chromosomes (frequency: 0.0139) from endocrine neoplasia-predisposition patients from the Netherlands who were negative for MEN1 mutations (Georgitsi_2007_PMID:17360484). The p.A299V variant was also identified in a family with familial isolated pituitary adenoma and was identified in two compound heterozygous asymptomatic males in this family who also carried the AIP p.R304* variant. Functional assessment of the effect of AIP binding with PDE4A5 did not demonstrate decreased binding compared to wildtype (Igreja_2010_PMID:20506337). The variant was identified in dbSNP (ID: rs148986773), ClinVar (classified as likely benign by GeneDx and Illumina and as uncertain significance by Ambry Genetics) and LOVD 3.0 (classified as likely benign and a VUS) but was not identified in Cosmic. The variant was identified in control databases in 152 of 279364 chromosomes at a frequency of 0.0005441 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 119 of 126880 chromosomes (freq: 0.000938), Other in 5 of 7124 chromosomes (freq: 0.000702), Latino in 20 of 35308 chromosomes (freq: 0.000566) and African in 8 of 24522 chromosomes (freq: 0.000326), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. Expression of the p.A299V AIP protein expressed in HEK293 cells demonstrated a decreased half-life compared to expression of WT AIP (Hernández-Ramírez_2016_PMID:27253664). The p.Ala240 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely 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).