rs118204096
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000190.4(HMBS):c.518G>A(p.Arg173Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R173W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000190.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HMBS | NM_000190.4 | c.518G>A | p.Arg173Gln | missense_variant | 9/14 | ENST00000652429.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HMBS | ENST00000652429.1 | c.518G>A | p.Arg173Gln | missense_variant | 9/14 | NM_000190.4 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000143 AC: 2AN: 1399378Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1AN XY: 690202
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Encephalopathy, porphyria-related Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1992 | - - |
Acute intermittent porphyria Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1992 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 17, 2023 | ClinVar contains an entry for this variant (Variation ID: 1447). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg173 amino acid residue in HMBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301948, 7635464, 11399210, 15643298, 23815679). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects HMBS function (PMID: 9281416). 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 HMBS protein function. This missense change has been observed in individual(s) with acute intermittent porphyria (PMID: 2243128, 9281416). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 173 of the HMBS protein (p.Arg173Gln). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at