chr11-119091413-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000190.4(HMBS):c.499C>T(p.Arg167Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 1,398,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R167L) has been classified as Pathogenic.
Frequency
Consequence
NM_000190.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HMBS | NM_000190.4 | c.499C>T | p.Arg167Trp | missense_variant, splice_region_variant | 9/14 | ENST00000652429.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HMBS | ENST00000652429.1 | c.499C>T | p.Arg167Trp | missense_variant, splice_region_variant | 9/14 | NM_000190.4 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000384 AC: 6AN: 156320Hom.: 0 AF XY: 0.0000243 AC XY: 2AN XY: 82266
GnomAD4 exome AF: 0.0000179 AC: 25AN: 1398000Hom.: 0 Cov.: 30 AF XY: 0.0000145 AC XY: 10AN XY: 689650
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Acute intermittent porphyria Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 24, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2004 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 21, 2019 | Published functional studies demonstrate a damaging effect on enzyme kinetics, resulting in 1-5% of normal enzyme activity and leading to an accumulation of porphyrin precursors (Bustad et al., 2013; Solis et al., 2004; Chen et al., 2016).; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11202057, 1577472, 15534187, 23815679, 12699244, 27539938, 11055586, 1301948, 2243128, 15643298, 15003823, 1496994) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 06, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 167 of the HMBS protein (p.Arg167Trp). This variant is present in population databases (rs118204101, gnomAD 0.02%). This missense change has been observed in individuals with acute intermittent porphyria (PMID: 1496994, 1577472, 15003823, 15534187, 15643298, 23815679). ClinVar contains an entry for this variant (Variation ID: 1456). 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 disruptive. Experimental studies have shown that this missense change affects HMBS function (PMID: 1496994, 11055586, 23815679, 27539938). This variant disrupts the p.Arg167 amino acid residue in HMBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1496994, 1577472, 2243128, 7962538, 9199558, 12372055, 15003823, 15643298, 23815679). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Encephalopathy, porphyria-related Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2004 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at