chr11-67487080-G-C
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_003977.4(AIP):āc.174G>Cā(p.Lys58Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K58R) has been classified as Uncertain significance.
Frequency
Consequence
NM_003977.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AIP | NM_003977.4 | c.174G>C | p.Lys58Asn | missense_variant | 2/6 | ENST00000279146.8 | |
AIP | NM_001302960.2 | c.174G>C | p.Lys58Asn | missense_variant | 2/6 | ||
AIP | NM_001302959.2 | c.-4G>C | 5_prime_UTR_variant | 2/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AIP | ENST00000279146.8 | c.174G>C | p.Lys58Asn | missense_variant | 2/6 | 1 | NM_003977.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251418Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135916
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461782Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14AN XY: 727182
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74368
ClinVar
Submissions by phenotype
Somatotroph adenoma Uncertain:2Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 19, 2023 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The API c.174G>C (p.Lys58Asn) missense variant has been reported in at least two studies in which it is found in two patients with pituitary macroadenoma in a heterozygous state (Tichomirowa et al. 2011; Cazabat L. 2012). The p.Lys58Asn variant was absent from 360 controls but is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium, though this is based on only two alleles but in a region of good sequence coverage. Based on the limited evidence, p.Lys58Asn variant is classified as a variant of uncertain significance but suspicious for pathogenicity for familial isolated pituitary adenomas. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 58 of the AIP protein (p.Lys58Asn). This variant is present in population databases (rs267606539, gnomAD 0.002%). This missense change has been observed in individual(s) with pituitary adenoma (PMID: 21753072, 22319033, 23321498). ClinVar contains an entry for this variant (Variation ID: 41166). 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 not expected to disrupt AIP protein function with a negative predictive value of 80%. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 15, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with isolated sporadic pituitary adenomas (Tichomirowa et al., 2011; Cazabat et al., 2012); This variant is associated with the following publications: (PMID: 21753072, 23371967, 22319033, 23321498, 31351448) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 25, 2024 | The p.K58N variant (also known as c.174G>C), located in coding exon 2 of the AIP gene, results from a G to C substitution at nucleotide position 174. The lysine at codon 58 is replaced by asparagine, an amino acid with similar properties. This alteration has been reported in multiple individuals with pituitary macroadenoma (Tichomirowa MA et al. Eur. J. Endocrinol., 2011 Oct;165:509-15; Cazabat L et al. J. Clin. Endocrinol. Metab., 2012 Apr;97:E663-70; Cuny T et al. Eur. J. Endocrinol., 2013 Apr;168:533-41; Nguyen JT et al. Front Endocrinol (Lausanne), 2024 Feb;15:1337741). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at