rs2066462

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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

Publications

43 publications found

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 Gene-Disease associations (from GenCC):

homocystinuria due to methylene tetrahydrofolate reductase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

MTHFR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 292238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

GnomAD2 exomes

AF:

0.0987

AC:

24778

AN:

251112

AF XY:

0.101

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 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

African (AFR)

AF:

0.0802

AC:

2685

AN:

33472

American (AMR)

AF:

0.0638

AC:

2851

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0333

AC:

871

AN:

26128

East Asian (EAS)

AF:

0.105

AC:

4176

AN:

39682

South Asian (SAS)

AF:

0.143

AC:

12323

AN:

86246

European-Finnish (FIN)

AF:

0.114

AC:

6097

AN:

53360

Middle Eastern (MID)

AF:

0.0449

AC:

259

AN:

5764

European-Non Finnish (NFE)

AF:

0.105

AC:

116826

AN:

1111548

Other (OTH)

AF:

0.105

AC:

6336

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

7351

14702

22053

29404

36755

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4332

8664

12996

17328

21660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0974

AC:

14825

AN:

152238

Hom.:

777

Cov.:

AF XY:

0.0985

AC XY:

7329

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0884

AC:

3672

AN:

41546

American (AMR)

AF:

0.0674

AC:

1032

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0326

AC:

113

AN:

3468

East Asian (EAS)

AF:

0.119

AC:

616

AN:

5168

South Asian (SAS)

AF:

0.158

AC:

763

AN:

4828

European-Finnish (FIN)

AF:

0.128

AC:

1356

AN:

10600

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.104

AC:

7041

AN:

68000

Other (OTH)

AF:

0.0827

AC:

175

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

690

1381

2071

2762

3452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

360

540

720

900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0944

Hom.:

329

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, 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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Benign:3

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

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

(source)

DANN

Benign

0.79

PhyloP100

-0.56

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over