11-67487051-G-A
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_003977.4(AIP):c.145G>A(p.Val49Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,613,944 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V49L) has been classified as Uncertain significance.
Frequency
Consequence
NM_003977.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AIP | NM_003977.4 | c.145G>A | p.Val49Met | missense_variant | 2/6 | ENST00000279146.8 | |
AIP | NM_001302960.2 | c.145G>A | p.Val49Met | missense_variant | 2/6 | ||
AIP | NM_001302959.2 | c.-33G>A | 5_prime_UTR_variant | 2/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AIP | ENST00000279146.8 | c.145G>A | p.Val49Met | missense_variant | 2/6 | 1 | NM_003977.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152216Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000275 AC: 69AN: 251326Hom.: 0 AF XY: 0.000250 AC XY: 34AN XY: 135912
GnomAD4 exome AF: 0.000153 AC: 224AN: 1461728Hom.: 1 Cov.: 32 AF XY: 0.000143 AC XY: 104AN XY: 727156
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7AN XY: 74356
ClinVar
Submissions by phenotype
Somatotroph adenoma Uncertain:1Benign:1Other:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 28, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies are inconclusive: reduced protein stability, inhibited interaction with RET and casp3, and no impact on interaction with PDE4A5 (PMID: 20506337, 27267386, 27253664, 28255869, 34588620); Observed in an individual with gigantism and a somatotrophinoma, which did not show loss of heterozygosity for the AIP V49M allele in tumor tissue (PMID: 17371465); This variant is associated with the following publications: (PMID: 30262796, 34426522, 27253664, 27267386, 21984905, 20506337, 20457215, 21348957, 34588620, 18381572, 28255869, 30941100, 17371465) - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 25, 2020 | 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. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 23, 2021 | - - |
AIP-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 29, 2023 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at