rs118204094
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000190.4(HMBS):c.346C>T(p.Arg116Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,738 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. R116Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000190.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HMBS | NM_000190.4 | c.346C>T | p.Arg116Trp | missense_variant, splice_region_variant | 7/14 | ENST00000652429.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HMBS | ENST00000652429.1 | c.346C>T | p.Arg116Trp | missense_variant, splice_region_variant | 7/14 | NM_000190.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251466Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135914
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460550Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726714
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74342
ClinVar
Submissions by phenotype
Acute intermittent porphyria Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1993 | - - |
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Sep 26, 2022 | PS3_Moderate, PS4, PM2_Supporting, PP1_Strong, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The c.346C>T (p.Arg116Trp) variant in HMBS gene has been observed in several families affected with acute intermittent porphyria (Bustad et al., 2013; de Rooij et al., 2009) and has been described as a founder mutation in the Dutch population (de Rooij et al., 2009). This variant has been reported to affect HMBS protein function (Bustad et al., 2013). This variant is reported with the allele frequency (0.0003%) in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Arg at position 116 is changed to a Trp changing protein sequence and it might alter its composition and physicochemical properties. The amino acid change p.Arg116Trp in HMBS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 116 of the HMBS protein (p.Arg116Trp). This variant is present in population databases (rs118204094, gnomAD 0.0009%). This missense change has been observed in individual(s) with acute intermittent porphyria (AIP) (PMID: 8096492, 19656453, 23815679). It is commonly reported in individuals of Dutch ancestry (PMID: 19656453). ClinVar contains an entry for this variant (Variation ID: 1445). 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: 9281416, 23815679). This variant disrupts the p.Arg116 amino acid residue in HMBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8081367). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 18, 2022 | Published functional studies demonstrate R116W abolishes enzymatic activity in vitro which is likely due to severe conformational instability of the variant (Bustad et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29360981, 9281416, 14757946, 23815679, 19656453, 27507172, 8096492) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 24, 2022 | PP3, PP4, PS3, PS4 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at