chr11-67483198-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 12P and 4B. PVS1_StrongPP5_Very_StrongBS2
The NM_003977.4(AIP):c.40C>T(p.Gln14*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,080 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 Pathogenic (★★).
Frequency
Consequence
NM_003977.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AIP | NM_003977.4 | c.40C>T | p.Gln14* | stop_gained | Exon 1 of 6 | ENST00000279146.8 | NP_003968.3 | |
AIP | NM_001302960.2 | c.40C>T | p.Gln14* | stop_gained | Exon 1 of 6 | NP_001289889.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251442Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135922
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461864Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727236
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74354
ClinVar
Submissions by phenotype
Pituitary adenoma predisposition Pathogenic:1
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Somatotroph adenoma Pathogenic:1
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not provided Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 4886). This premature translational stop signal has been observed in individual(s) with pituitary adenoma (PMID: 16728643). This variant is present in population databases (rs104894194, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Gln14*) in the AIP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AIP are known to be pathogenic (PMID: 23321498, 26186299). -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.Q14* pathogenic mutation (also known as c.40C>T), located in coding exon 1 of the AIP gene, results from a C to T substitution at nucleotide position 40. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This mutation has been reported in multiple individuals, predominantly of Finnish descent, with familial isolated pituitary adenomas (Vierimaa O et al. Science 2006 May;312(5777):1228-30; Georgitsi M et al. Proc. Natl. Acad. Sci. U.S.A. 2007 Mar;104(10):4101-5; Beckers A et al. Endocr. Rev. 2013 Apr;34(2):239-77). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at