11-119089747-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000190.4(HMBS):c.331G>A(p.Gly111Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000190.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HMBS | NM_000190.4 | c.331G>A | p.Gly111Arg | missense_variant | 6/14 | ENST00000652429.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HMBS | ENST00000652429.1 | c.331G>A | p.Gly111Arg | missense_variant | 6/14 | NM_000190.4 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460334Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726398
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Acute intermittent porphyria Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jun 01, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1994 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 111 of the HMBS protein (p.Gly111Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with acute intermittent porphyria (PMID: 8268934, 11399210, 11857754). ClinVar contains an entry for this variant (Variation ID: 1464). 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 HMBS protein function. Experimental studies have shown that this missense change affects HMBS function (PMID: 8268934, 29360981). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at