rs121917852
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_002181.4(IHH):c.283G>A(p.Glu95Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E95G) has been classified as Pathogenic.
Frequency
Consequence
NM_002181.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IHH | NM_002181.4 | c.283G>A | p.Glu95Lys | missense_variant | 1/3 | ENST00000295731.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IHH | ENST00000295731.7 | c.283G>A | p.Glu95Lys | missense_variant | 1/3 | 1 | NM_002181.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Brachydactyly type A1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 30, 2009 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 27, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects IHH function (PMID: 19252479). 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 IHH protein function. ClinVar contains an entry for this variant (Variation ID: 8866). This missense change has been observed in individuals with brachydactyly (PMID: 11455389; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 95 of the IHH protein (p.Glu95Lys). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at