dbSNP rs17037390: MTHFR:c.475+375C>T (chr1-11800786-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005957.5(MTHFR):c.475+375C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 395,534 control chromosomes in the GnomAD database, including 5,572 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.17 ( 2454 hom., cov: 32)

Exomes 𝑓: 0.16 ( 3118 hom. )

Consequence

MTHFR
NM_005957.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.246

Publications

30 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 -12 ACMG points.

BP4

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

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5 link	c.475+375C>T		intron_variant	Intron 3 of 11	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9 link	c.475+375C>T		intron_variant	Intron 3 of 11	1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes

AF:

0.173

AC:

26326

AN:

151988

Hom.:

2450

Cov.:

show subpopulations

Gnomad AFR

AF:

0.231

Gnomad AMI

AF:

0.0844

Gnomad AMR

AF:

0.122

Gnomad ASJ

AF:

0.0942

Gnomad EAS

AF:

0.126

Gnomad SAS

AF:

0.200

Gnomad FIN

AF:

0.162

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.159

Gnomad OTH

AF:

0.151

GnomAD4 exome

AF:

0.156

AC:

37930

AN:

243428

Hom.:

3118

Cov.:

AF XY:

0.158

AC XY:

20652

AN XY:

131106

show subpopulations

African (AFR)

AF:

0.235

AC:

1673

AN:

7126

American (AMR)

AF:

0.112

AC:

1281

AN:

11418

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

650

AN:

6428

East Asian (EAS)

AF:

0.118

AC:

1353

AN:

11514

South Asian (SAS)

AF:

0.181

AC:

7335

AN:

40618

European-Finnish (FIN)

AF:

0.145

AC:

1764

AN:

12144

Middle Eastern (MID)

AF:

0.151

AC:

140

AN:

926

European-Non Finnish (NFE)

AF:

0.155

AC:

21732

AN:

140522

Other (OTH)

AF:

0.157

AC:

2002

AN:

12732

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1640

3280

4921

6561

8201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

368

552

736

920

<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:

0.173

AC:

26352

AN:

152106

Hom.:

2454

Cov.:

AF XY:

0.174

AC XY:

12910

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.231

AC:

9586

AN:

41440

American (AMR)

AF:

0.121

AC:

1854

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0942

AC:

327

AN:

3470

East Asian (EAS)

AF:

0.125

AC:

649

AN:

5172

South Asian (SAS)

AF:

0.200

AC:

963

AN:

4820

European-Finnish (FIN)

AF:

0.162

AC:

1711

AN:

10588

Middle Eastern (MID)

AF:

0.129

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.159

AC:

10821

AN:

68008

Other (OTH)

AF:

0.154

AC:

326

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1103

2207

3310

4414

5517

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

294

588

882

1176

1470

<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:

0.156

Hom.:

2719

Bravo

AF:

0.171

Asia WGS

AF:

0.170

AC:

590

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.8

(source)

DANN

Benign

0.79

PhyloP100

-0.25

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over