rs781158269
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_005957.5(MTHFR):āc.330G>Cā(p.Met110Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 32)
Exomes š: 0.000037 ( 0 hom. )
Consequence
MTHFR
NM_005957.5 missense
NM_005957.5 missense
Scores
2
8
9
Clinical Significance
Conservation
PhyloP100: 7.25
Genes affected
MTHFR (HGNC:7436): (methylenetetrahydrofolate reductase) The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.10294202).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTHFR | NM_005957.5 | c.330G>C | p.Met110Ile | missense_variant | 3/12 | ENST00000376590.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTHFR | ENST00000376590.9 | c.330G>C | p.Met110Ile | missense_variant | 3/12 | 1 | NM_005957.5 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152202Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
3
AN:
152202
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000111 AC: 28AN: 251436Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135902
GnomAD3 exomes
AF:
AC:
28
AN:
251436
Hom.:
AF XY:
AC XY:
17
AN XY:
135902
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000369 AC: 54AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26AN XY: 727242
GnomAD4 exome
AF:
AC:
54
AN:
1461888
Hom.:
Cov.:
31
AF XY:
AC XY:
26
AN XY:
727242
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74356
GnomAD4 genome
AF:
AC:
3
AN:
152202
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74356
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ExAC
AF:
AC:
15
Asia WGS
AF:
AC:
2
AN:
3478
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Homocystinuria due to methylene tetrahydrofolate reductase deficiency Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2021 | This sequence change replaces methionine with isoleucine at codon 110 of the MTHFR protein (p.Met110Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs781158269, ExAC 0.2%). This variant has not been reported in the literature in individuals affected with MTHFR-related conditions. ClinVar contains an entry for this variant (Variation ID: 572237). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects MTHFR function (PMID: 18523009). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
MTHFR-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 03, 2023 | The MTHFR c.330G>C variant is predicted to result in the amino acid substitution p.Met110Ile. This variant was reported in an individual with pulmonary embolism (Tan et al. 2021. PubMed ID: 33571559). This variant is reported in 0.14% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-11861363-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;D;.;.;.;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;T;.;T;T;T;D;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;.;.;L;.;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;.;.;.;N
REVEL
Uncertain
Sift
Benign
T;T;T;T;.;.;.;T
Sift4G
Benign
T;T;T;T;.;.;.;.
Polyphen
B;.;.;B;.;.;.;.
Vest4
MutPred
Loss of catalytic residue at M110 (P = 0.0024);.;.;Loss of catalytic residue at M110 (P = 0.0024);.;Loss of catalytic residue at M110 (P = 0.0024);Loss of catalytic residue at M110 (P = 0.0024);Loss of catalytic residue at M110 (P = 0.0024);
MVP
MPC
ClinPred
T
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