Genetic Variant ENST00000431243.6:n.38A>G (chr1-11804529-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 ENST00000431243.6(MTHFR):n.38A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 150,732 control chromosomes in the GnomAD database, including 1,624 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 0.14 ( 1623 hom., cov: 32)

Exomes 𝑓: 0.12 ( 1 hom. )

Consequence

MTHFR
ENST00000431243.6 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.321

Publications

39 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=-0.85).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5 link	c.-14+1359A>G		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.-14+1359A>G		intron_variant	Intron 1 of 11	1	NM_005957.5	ENSP00000365775.3		P42898-1

Frequencies

GnomAD3 genomes

AF:

0.143

AC:

21540

AN:

150614

Hom.:

1624

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.0844

Gnomad AMR

AF:

0.110

Gnomad ASJ

AF:

0.0861

Gnomad EAS

AF:

0.126

Gnomad SAS

AF:

0.201

Gnomad FIN

AF:

0.166

Gnomad MID

AF:

0.118

Gnomad NFE

AF:

0.157

Gnomad OTH

AF:

0.129

GnomAD4 exome

AF:

0.121

AC:

AN:

Hom.:

Cov.:

AF XY:

0.100

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.0625

AC:

AN:

European-Finnish (FIN)

AF:

0.250

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.136

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.143

AC:

21548

AN:

150666

Hom.:

1623

Cov.:

AF XY:

0.144

AC XY:

10599

AN XY:

73488

show subpopulations

African (AFR)

AF:

0.129

AC:

5308

AN:

41082

American (AMR)

AF:

0.110

AC:

1661

AN:

15146

Ashkenazi Jewish (ASJ)

AF:

0.0861

AC:

298

AN:

3460

East Asian (EAS)

AF:

0.126

AC:

652

AN:

5156

South Asian (SAS)

AF:

0.201

AC:

961

AN:

4778

European-Finnish (FIN)

AF:

0.166

AC:

1655

AN:

9974

Middle Eastern (MID)

AF:

0.127

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.157

AC:

10622

AN:

67776

Other (OTH)

AF:

0.133

AC:

277

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

973

1947

2920

3894

4867

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.144

Hom.:

2186

Bravo

AF:

0.136

Asia WGS

AF:

0.162

AC:

562

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

0.32

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

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

Publications

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ENST00000431243.6:n.38A>G

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