Genetic Variant ENST00000376592.6:c.-731G>A (chr1-11803847-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000376592.6(MTHFR):c.-731G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0988 in 296,594 control chromosomes in the GnomAD database, including 1,558 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 0.098 ( 792 hom., cov: 32)

Exomes 𝑓: 0.099 ( 766 hom. )

Consequence

MTHFR
ENST00000376592.6 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.179

Publications

8 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=-0.76).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5 link	c.-13-718G>A		intron_variant	Intron 1 of 11	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.-13-718G>A		intron_variant	Intron 1 of 11	1	NM_005957.5	ENSP00000365775.3		P42898-1

Frequencies

GnomAD3 genomes

AF:

0.0985

AC:

14979

AN:

152056

Hom.:

795

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0947

Gnomad AMI

AF:

0.0484

Gnomad AMR

AF:

0.0676

Gnomad ASJ

AF:

0.0317

Gnomad EAS

AF:

0.124

Gnomad SAS

AF:

0.157

Gnomad FIN

AF:

0.126

Gnomad MID

AF:

0.0382

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.0821

GnomAD4 exome

AF:

0.0993

AC:

14339

AN:

144420

Hom.:

766

Cov.:

AF XY:

0.101

AC XY:

7500

AN XY:

74614

show subpopulations

African (AFR)

AF:

0.101

AC:

330

AN:

3280

American (AMR)

AF:

0.0653

AC:

254

AN:

3888

Ashkenazi Jewish (ASJ)

AF:

0.0321

AC:

151

AN:

4710

East Asian (EAS)

AF:

0.0988

AC:

595

AN:

6024

South Asian (SAS)

AF:

0.132

AC:

2165

AN:

16374

European-Finnish (FIN)

AF:

0.107

AC:

1054

AN:

9822

Middle Eastern (MID)

AF:

0.0484

AC:

AN:

702

European-Non Finnish (NFE)

AF:

0.0977

AC:

8832

AN:

90376

Other (OTH)

AF:

0.100

AC:

924

AN:

9244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

601

1202

1804

2405

3006

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.0984

AC:

14976

AN:

152174

Hom.:

792

Cov.:

AF XY:

0.0994

AC XY:

7391

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0945

AC:

3924

AN:

41518

American (AMR)

AF:

0.0672

AC:

1027

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0317

AC:

110

AN:

3468

East Asian (EAS)

AF:

0.124

AC:

642

AN:

5190

South Asian (SAS)

AF:

0.157

AC:

757

AN:

4818

European-Finnish (FIN)

AF:

0.126

AC:

1337

AN:

10590

Middle Eastern (MID)

AF:

0.0445

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.102

AC:

6948

AN:

67994

Other (OTH)

AF:

0.0822

AC:

174

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

691

1382

2073

2764

3455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

178

356

534

712

890

<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:

0.0969

Hom.:

108

Bravo

AF:

0.0921

Asia WGS

AF:

0.128

AC:

445

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

5.3

(source)

DANN

Benign

0.65

PhyloP100

0.18

PromoterAI

-0.11

Neutral

(source)

Mutation Taster

=299/1

polymorphism (auto)

(source)

Splicing

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