rs2066470

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005957.5(MTHFR):c.117C>T(p.Pro39Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,613,948 control chromosomes in the GnomAD database, including 8,874 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.093 ( 708 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8166 hom. )

Consequence

MTHFR
NM_005957.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -7.56

Publications

61 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 1-11803000-G-A is Benign according to our data. Variant chr1-11803000-G-A is described in ClinVar as Benign. ClinVar VariationId is 292246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-7.56 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5 link	c.117C>T	p.Pro39Pro	synonymous_variant	Exon 2 of 12	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9 link	c.117C>T	p.Pro39Pro	synonymous_variant	Exon 2 of 12	1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes

AF:

0.0930

AC:

14147

AN:

152076

Hom.:

711

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0779

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.0650

Gnomad ASJ

AF:

0.0317

Gnomad EAS

AF:

0.124

Gnomad SAS

AF:

0.156

Gnomad FIN

AF:

0.126

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.101

Gnomad OTH

AF:

0.0766

GnomAD2 exomes

AF:

0.0976

AC:

24504

AN:

251096

AF XY:

0.0997

show subpopulations

Gnomad AFR exome

AF:

0.0752

Gnomad AMR exome

AF:

0.0622

Gnomad ASJ exome

AF:

0.0339

Gnomad EAS exome

AF:

0.122

Gnomad FIN exome

AF:

0.116

Gnomad NFE exome

AF:

0.0977

Gnomad OTH exome

AF:

0.0869

GnomAD4 exome

AF:

0.103

AC:

151010

AN:

1461754

Hom.:

8166

Cov.:

AF XY:

0.104

AC XY:

75660

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.0781

AC:

2616

AN:

33480

American (AMR)

AF:

0.0623

AC:

2785

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0343

AC:

896

AN:

26128

East Asian (EAS)

AF:

0.109

AC:

4324

AN:

39700

South Asian (SAS)

AF:

0.143

AC:

12322

AN:

86232

European-Finnish (FIN)

AF:

0.112

AC:

5982

AN:

53410

Middle Eastern (MID)

AF:

0.0432

AC:

249

AN:

5768

European-Non Finnish (NFE)

AF:

0.104

AC:

115567

AN:

1111928

Other (OTH)

AF:

0.104

AC:

6269

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

9029

18059

27088

36118

45147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4318

8636

12954

17272

21590

<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:

0.0929

AC:

14144

AN:

152194

Hom.:

708

Cov.:

AF XY:

0.0944

AC XY:

7022

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0777

AC:

3228

AN:

41528

American (AMR)

AF:

0.0646

AC:

988

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0317

AC:

110

AN:

3472

East Asian (EAS)

AF:

0.124

AC:

641

AN:

5174

South Asian (SAS)

AF:

0.156

AC:

753

AN:

4818

European-Finnish (FIN)

AF:

0.126

AC:

1338

AN:

10586

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.101

AC:

6866

AN:

68012

Other (OTH)

AF:

0.0768

AC:

162

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

644

1289

1933

2578

3222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

344

516

688

860

<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:

0.0931

Hom.:

1382

Bravo

AF:

0.0859

Asia WGS

AF:

0.127

AC:

440

AN:

3478

EpiCase

AF:

0.0915

EpiControl

AF:

0.0854

ClinVar

Significance: Benign

Submissions summary: Benign:7

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

- -

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. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

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

-0.74

CADD

Benign

0.20

(source)

DANN

Benign

0.90

PhyloP100

-7.6

PromoterAI

0.0018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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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