rs121913579
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_ModeratePP5_Moderate
The NM_000254.3(MTR):āc.2758C>Gā(p.His920Asp) 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. Variant has been reported in ClinVar as Likely pathogenic (ā ). Synonymous variant affecting the same amino acid position (i.e. H920H) has been classified as Likely benign.
Frequency
Consequence
NM_000254.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTR | NM_000254.3 | c.2758C>G | p.His920Asp | missense_variant | 26/33 | ENST00000366577.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTR | ENST00000366577.10 | c.2758C>G | p.His920Asp | missense_variant | 26/33 | 1 | NM_000254.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251226Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135810
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.97e-7 AC: 1AN: 1435088Hom.: 0 Cov.: 28 AF XY: 0.00000140 AC XY: 1AN XY: 715838
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Methylcobalamin deficiency type cblG Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2023 | This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 920 of the MTR protein (p.His920Asp). This variant is present in population databases (rs121913579, gnomAD 0.0009%). This missense change has been observed in individual(s) with cobalamin G deficiency and/or methionine synthase deficiency (PMID: 8968737, 34625984; Invitae). ClinVar contains an entry for this variant (Variation ID: 14280). 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 MTR protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1996 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at