dbSNP rs2184226: MTHFR:c.*3301A>G (chr1-11787379-T-C) – 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.*3301A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0788 in 1,281,526 control chromosomes in the GnomAD database, including 4,186 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 0.071 ( 428 hom., cov: 33)

Exomes 𝑓: 0.080 ( 3758 hom. )

Consequence

MTHFR
NM_005957.5 3_prime_UTR

Scores

Splicing: ADA: 0.0001432

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0490

Publications

28 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 links:

C1orf167 (HGNC:25262): (chromosome 1 open reading frame 167) Implicated in coronary artery disease. [provided by Alliance of Genome Resources, Apr 2022]

C1orf167 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=-0.78).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5 link	c.*3301A>G		3_prime_UTR_variant	Exon 12 of 12	ENST00000376590.9	NP_005948.3
C1orf167	NM_001010881.2 link	c.3568-9T>C		intron_variant	Intron 16 of 20	ENST00000688073.1	NP_001010881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9 link	c.*3301A>G		3_prime_UTR_variant	Exon 12 of 12	1	NM_005957.5	ENSP00000365775.3
C1orf167	ENST00000688073.1 link	c.3568-9T>C		intron_variant	Intron 16 of 20		NM_001010881.2	ENSP00000510540.1

Frequencies

GnomAD3 genomes

AF:

0.0713

AC:

10843

AN:

152168

Hom.:

427

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0784

Gnomad AMI

AF:

0.0954

Gnomad AMR

AF:

0.0578

Gnomad ASJ

AF:

0.0487

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0828

Gnomad FIN

AF:

0.0350

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0803

Gnomad OTH

AF:

0.0871

GnomAD2 exomes

AF:

0.0649

AC:

8824

AN:

135982

AF XY:

0.0683

show subpopulations

Gnomad AFR exome

AF:

0.0777

Gnomad AMR exome

AF:

0.0458

Gnomad ASJ exome

AF:

0.0588

Gnomad EAS exome

AF:

0.000403

Gnomad FIN exome

AF:

0.0381

Gnomad NFE exome

AF:

0.0796

Gnomad OTH exome

AF:

0.0755

GnomAD4 exome

AF:

0.0799

AC:

90170

AN:

1129240

Hom.:

3758

Cov.:

AF XY:

0.0811

AC XY:

44763

AN XY:

552138

show subpopulations

African (AFR)

AF:

0.0854

AC:

2026

AN:

23724

American (AMR)

AF:

0.0457

AC:

1152

AN:

25184

Ashkenazi Jewish (ASJ)

AF:

0.0587

AC:

873

AN:

14866

East Asian (EAS)

AF:

0.000245

AC:

AN:

12238

South Asian (SAS)

AF:

0.0940

AC:

6933

AN:

73780

European-Finnish (FIN)

AF:

0.0357

AC:

915

AN:

25664

Middle Eastern (MID)

AF:

0.126

AC:

529

AN:

4206

European-Non Finnish (NFE)

AF:

0.0821

AC:

74608

AN:

909088

Other (OTH)

AF:

0.0773

AC:

3131

AN:

40490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

4230

8461

12691

16922

21152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3262

6524

9786

13048

16310

<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:

0.0713

AC:

10856

AN:

152286

Hom.:

428

Cov.:

AF XY:

0.0694

AC XY:

5170

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0786

AC:

3268

AN:

41564

American (AMR)

AF:

0.0577

AC:

882

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0487

AC:

169

AN:

3470

East Asian (EAS)

AF:

0.000771

AC:

AN:

5186

South Asian (SAS)

AF:

0.0825

AC:

398

AN:

4826

European-Finnish (FIN)

AF:

0.0350

AC:

372

AN:

10620

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0803

AC:

5461

AN:

68004

Other (OTH)

AF:

0.0862

AC:

182

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

506

1013

1519

2026

2532

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<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:

0.0777

Hom.:

1094

Bravo

AF:

0.0737

Asia WGS

AF:

0.0380

AC:

133

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

7.2

(source)

DANN

Benign

0.77

PhyloP100

-0.049

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.15

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