Genetic Variant MTHFR:c.*372A>C (chr1-11790308-T-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005957.5(MTHFR):c.*372A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.662 in 530,354 control chromosomes in the GnomAD database, including 118,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.63 ( 31086 hom., cov: 33)

Exomes 𝑓: 0.67 ( 87058 hom. )

Consequence

MTHFR
NM_005957.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.874

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 1-11790308-T-G is Benign according to our data. Variant chr1-11790308-T-G is described in ClinVar as [Benign]. Clinvar id is 292223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5 link	c.*372A>C		3_prime_UTR_variant	Exon 12 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.*372A>C		3_prime_UTR_variant	Exon 12 of 12	1	NM_005957.5	ENSP00000365775.3		P42898-1

Frequencies

GnomAD3 genomes

AF:

0.632

AC:

96038

AN:

151972

Hom.:

31075

Cov.:

show subpopulations

Gnomad AFR

AF:

0.494

Gnomad AMI

AF:

0.712

Gnomad AMR

AF:

0.751

Gnomad ASJ

AF:

0.685

Gnomad EAS

AF:

0.775

Gnomad SAS

AF:

0.545

Gnomad FIN

AF:

0.671

Gnomad MID

AF:

0.589

Gnomad NFE

AF:

0.674

Gnomad OTH

AF:

0.655

GnomAD4 exome

AF:

0.674

AC:

254913

AN:

378264

Hom.:

87058

Cov.:

AF XY:

0.670

AC XY:

130689

AN XY:

195180

show subpopulations

African (AFR)

AF:

0.503

AC:

5898

AN:

11718

American (AMR)

AF:

0.775

AC:

11235

AN:

14496

Ashkenazi Jewish (ASJ)

AF:

0.693

AC:

8505

AN:

12280

East Asian (EAS)

AF:

0.798

AC:

23517

AN:

29468

South Asian (SAS)

AF:

0.539

AC:

13840

AN:

25664

European-Finnish (FIN)

AF:

0.686

AC:

18584

AN:

27106

Middle Eastern (MID)

AF:

0.599

AC:

1066

AN:

1780

European-Non Finnish (NFE)

AF:

0.675

AC:

157054

AN:

232780

Other (OTH)

AF:

0.662

AC:

15214

AN:

22972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

3947

7895

11842

15790

19737

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.632

AC:

96088

AN:

152090

Hom.:

31086

Cov.:

AF XY:

0.632

AC XY:

47033

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.494

AC:

20466

AN:

41464

American (AMR)

AF:

0.751

AC:

11480

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.685

AC:

2377

AN:

3470

East Asian (EAS)

AF:

0.775

AC:

4002

AN:

5164

South Asian (SAS)

AF:

0.544

AC:

2624

AN:

4824

European-Finnish (FIN)

AF:

0.671

AC:

7108

AN:

10588

Middle Eastern (MID)

AF:

0.592

AC:

174

AN:

294

European-Non Finnish (NFE)

AF:

0.674

AC:

45829

AN:

67980

Other (OTH)

AF:

0.653

AC:

1379

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1755

3510

5264

7019

8774

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.619

Hom.:

13991

Bravo

AF:

0.636

Asia WGS

AF:

0.641

AC:

2229

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.24

(source)

DANN

Benign

0.48

PhyloP100

-0.87

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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1-11790308-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over