1-236885202-C-G
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_ModeratePP5_Moderate
The NM_000254.3(MTR):c.2758C>G(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 (★). Synonymous variant affecting the same amino acid position (i.e. H920H) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 7.0e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
MTR
NM_000254.3 missense
NM_000254.3 missense
Scores
9
7
1
Clinical Significance
Conservation
PhyloP100: 7.22
Genes affected
MTR (HGNC:7468): (5-methyltetrahydrofolate-homocysteine methyltransferase) This gene encodes the 5-methyltetrahydrofolate-homocysteine methyltransferase. This enzyme, also known as cobalamin-dependent methionine synthase, catalyzes the final step in methionine biosynthesis. Mutations in MTR have been identified as the underlying cause of methylcobalamin deficiency complementation group G. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, MTR
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.938
PP5
?
Variant 1-236885202-C-G is Pathogenic according to our data. Variant chr1-236885202-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14280.Status of the report is criteria_provided_single_submitter, 1 stars.
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 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251226Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135810
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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 exome
Data not reliable, filtered out with message: AS_VQSR
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GnomAD4 genome ? Cov.: 33
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33
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
1.0
.;D;.
Vest4
MutPred
0.77
.;Gain of relative solvent accessibility (P = 0.0479);.;
MVP
MPC
1.5
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at