rs267606548
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_003977.4(AIP):c.308A>G(p.Lys103Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar 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 -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AIP | NM_003977.4 | c.308A>G | p.Lys103Arg | missense_variant | Exon 3 of 6 | ENST00000279146.8 | NP_003968.3 | |
AIP | NM_001302960.2 | c.308A>G | p.Lys103Arg | missense_variant | Exon 3 of 6 | NP_001289889.1 | ||
AIP | NM_001302959.2 | c.131A>G | p.Lys44Arg | missense_variant | Exon 3 of 6 | NP_001289888.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 247876Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134870
GnomAD4 exome AF: 0.00000480 AC: 7AN: 1459428Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4AN XY: 726042
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:2
Published functional studies are conflicting (Igreja 2010, Bolger 2016, Formosa 2017); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30764022, 21348957, 21512261, 23371967, 20457215, 25614825, 27267386, 28255869, 20507346, 20506337) -
This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 103 of the AIP protein (p.Lys103Arg). This variant is present in population databases (rs267606548, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of AIP-related conditions (PMID: 20507346, 36149413). ClinVar contains an entry for this variant (Variation ID: 41174). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on AIP function (PMID: 20506337, 28255869). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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. -
Somatotroph adenoma Uncertain:1Other:1
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Hereditary cancer-predisposing syndrome Uncertain:1
The p.K103R variant (also known as c.308A>G), located in coding exon 3 of the AIP gene, results from an A to G substitution at nucleotide position 308. The lysine at codon 103 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with personal and/or family history consistent with Familial Isolated Pituitary Adenomas (FIPA) (Igreja S et al. Hum. Mutat. 2010 Aug;31:950-60; Stratakis CA et al. Clin. Genet. 2010 Nov;78:457-63; Guaraldi F et al. Clin Transl Sci. 2011 Feb;4:55-62; Beckers A et al. Endocr. Rev. 2013 Apr;34:239-77; Dinesen PT et al. Endocrinol Diabetes Metab Case Rep. 2015 Jan;2015:140105). Further, functional analysis using a yeast two-hybrid quantitative b-galactosidase assay assessed the interaction of AIP with PDE4A5, an AIP binding protein, and found that this alteration results in b-galactosidase assay activity values more than fivefold different from wild type suggesting that it leads to a complete loss of PDE4A5–AIP binding (Igreja S et al. Hum. Mutat. 2010 Aug;31:950-60). However another functional analysis using protein expression of the PDE4A5 rat homologue PDE4A4, suggests the p.K103R alteration has no clear inhibitory effect (Bolger GB et al. Endocr. Relat. Cancer, 2016 May;23:419-31). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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