rs2066462

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_005957.5(MTHFR):c.1056C>T(p.Ser352Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,613,510 control chromosomes in the GnomAD database, including 9,138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.097 ( 777 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8361 hom. )

Consequence

MTHFR
NM_005957.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.561

Variant links:

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]

MTHFR links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 1-11794839-G-A is Benign according to our data. Variant chr1-11794839-G-A is described in ClinVar as [Benign]. Clinvar id is 292238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11794839-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.561 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5 link	c.1056C>T	p.Ser352Ser	synonymous_variant	Exon 7 of 12	ENST00000376590.9	NP_005948.3	P42898-1Q8IU67Q59GJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9 link	c.1056C>T	p.Ser352Ser	synonymous_variant	Exon 7 of 12	1	NM_005957.5	ENSP00000365775.3		P42898-1

Frequencies

GnomAD3 genomes

AF:

0.0973

AC:

14805

AN:

152120

Hom.:

776

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0882

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.0674

Gnomad ASJ

AF:

0.0326

Gnomad EAS

AF:

0.119

Gnomad SAS

AF:

0.158

Gnomad FIN

AF:

0.128

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.104

Gnomad OTH

AF:

0.0826

GnomAD3 exomes

AF:

0.0987

AC:

24778

AN:

251112

Hom.:

1417

AF XY:

0.101

AC XY:

13672

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.0804

Gnomad AMR exome

AF:

0.0636

Gnomad ASJ exome

AF:

0.0321

Gnomad EAS exome

AF:

0.118

Gnomad SAS exome

AF:

0.144

Gnomad FIN exome

AF:

0.118

Gnomad NFE exome

AF:

0.0993

Gnomad OTH exome

AF:

0.0893

GnomAD4 exome

AF:

0.104

AC:

152424

AN:

1461272

Hom.:

8361

Cov.:

AF XY:

0.105

AC XY:

76360

AN XY:

726860

show subpopulations

Gnomad4 AFR exome

AF:

0.0802

Gnomad4 AMR exome

AF:

0.0638

Gnomad4 ASJ exome

AF:

0.0333

Gnomad4 EAS exome

AF:

0.105

Gnomad4 SAS exome

AF:

0.143

Gnomad4 FIN exome

AF:

0.114

Gnomad4 NFE exome

AF:

0.105

Gnomad4 OTH exome

AF:

0.105

GnomAD4 genome

AF:

0.0974

AC:

14825

AN:

152238

Hom.:

777

Cov.:

AF XY:

0.0985

AC XY:

7329

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0884

Gnomad4 AMR

AF:

0.0674

Gnomad4 ASJ

AF:

0.0326

Gnomad4 EAS

AF:

0.119

Gnomad4 SAS

AF:

0.158

Gnomad4 FIN

AF:

0.128

Gnomad4 NFE

AF:

0.104

Gnomad4 OTH

AF:

0.0827

Alfa

AF:

0.0943

Hom.:

325

Bravo

AF:

0.0891

Asia WGS

AF:

0.128

AC:

443

AN:

3478

EpiCase

AF:

0.0931

EpiControl

AF:

0.0872

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 25, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Benign:3

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

9.1

DANN

Benign

0.79

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over