rs267606579
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_003977.4(AIP):c.811C>T(p.Arg271Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R271Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_003977.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AIP | NM_003977.4 | c.811C>T | p.Arg271Trp | missense_variant | 6/6 | ENST00000279146.8 | |
AIP | NM_001302960.2 | c.803C>T | p.Ala268Val | missense_variant | 6/6 | ||
AIP | NM_001302959.2 | c.634C>T | p.Arg212Trp | missense_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AIP | ENST00000279146.8 | c.811C>T | p.Arg271Trp | missense_variant | 6/6 | 1 | NM_003977.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248938Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135278
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460118Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726378
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 29, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 271 of the AIP protein (p.Arg271Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with familial and sporadic pituitary adenomas (PMID: 17244780, 19684062, 21753072, 26186299). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41210). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AIP protein function. Experimental studies have shown that this missense change affects AIP function (PMID: 20506337, 27253664). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | AIP: PP1:Strong, PM2, PS4:Moderate, PP4, PS3:Supporting - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 04, 2023 | The p.R271W variant (also known as c.811C>T), located in coding exon 6 of the AIP gene, results from a C to T substitution at nucleotide position 811. The arginine at codon 271 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. This alteration has been identified in multiple individuals with a personal and/or family history of pituitary adenomas and segregates with disease in multiple families (De Sousa SMC et al. Eur J Endocrinol, 2017 May;176:635-644; Jennings JE et al. Eur J Endocrinol, 2009 Nov;161:799-804; Daly AF et al. J Clin Endocrinol Metab, 2007 May;92:1891-6; Ambry internal data). This alteration induced severely reduced protein half-life which was a suggested mechanism for tumorigenesis (Hernández-Ramírez LC et al. J Clin Endocrinol Metab, 2016 08;101:3144-54). Based on internal structural analysis, R271W is highly destabilizing to the structure near a region known to interact with several other proteins and disrupts hydrogen bonds which are important to the stability of the TPR domain fold (Morgan RM et al. PLoS One, 2012 Dec;7:e53339; Das AK et al. EMBO J, 1998 Mar;17:1192-9; Bolger GB et al. J Biol Chem, 2003 Aug;278:33351-63; Igreja S et al. Hum Mutat, 2010 Aug;31:950-60). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Somatotroph adenoma Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at