chr11-67490803-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_003977.4(AIP):c.803A>G(p.Tyr268Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,962 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y268H) has been classified as Uncertain significance.
Frequency
Consequence
NM_003977.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AIP | NM_003977.4 | c.803A>G | p.Tyr268Cys | missense_variant | 6/6 | ENST00000279146.8 | |
AIP | NM_001302959.2 | c.626A>G | p.Tyr209Cys | missense_variant | 6/6 | ||
AIP | NM_001302960.2 | c.795A>G | p.Leu265= | synonymous_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AIP | ENST00000279146.8 | c.803A>G | p.Tyr268Cys | missense_variant | 6/6 | 1 | NM_003977.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248862Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135232
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459962Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726300
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 268 of the AIP protein (p.Tyr268Cys). This variant is present in population databases (rs267606577, gnomAD 0.0009%). This missense change has been observed in individual(s) with a prolactinoma (PMID: 21753072). ClinVar contains an entry for this variant (Variation ID: 41206). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AIP protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 01, 2022 | The p.Y268C variant (also known as c.803A>G), located in coding exon 6 of the AIP gene, results from an A to G substitution at nucleotide position 803. The tyrosine at codon 268 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in individuals with apparent sporadic pituitary macroadenomas (Tichomirowa MA et al. Eur. J. Endocrinol., 2011 Oct;165:509-15; Beckers A et al. Endocr. Rev., 2013 Apr;34:239-77). This alteration is located in the functional significant tetratricopeptide repeat domain of the AIP protein, and a structural analysis suggests it may disrupt packing of the hydrophobic core (Morgan RM et al. PLoS ONE, 2012 Dec;7:e53339). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
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