Genetic Variant MTHFR:c.-14+128dupG (chr1-11805759-G-GC) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_005957.5(MTHFR):c.-14+128dupG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0978 in 155,862 control chromosomes in the GnomAD database, including 795 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.099 ( 788 hom., cov: 31)

Exomes 𝑓: 0.071 ( 7 hom. )

Consequence

MTHFR
NM_005957.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.03

Publications

2 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: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

MTHFR links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005957.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	NM_005957.5	MANE Select	c.-14+128dupG		intron	N/A	NP_005948.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.-14+128dupG	intron	N/A	ENSP00000365775.3	P42898-1
MTHFR	ENST00000376486.3	TSL:1	c.-11+128dupG	intron	N/A	ENSP00000365669.3	F8W9T8
MTHFR	ENST00000911085.1		c.-424dupG	5_prime_UTR	Exon 1 of 12	ENSP00000581144.1

Frequencies

GnomAD3 genomes

AF:

0.0986

AC:

14976

AN:

151864

Hom.:

791

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0947

Gnomad AMI

AF:

0.0484

Gnomad AMR

AF:

0.0682

Gnomad ASJ

AF:

0.0314

Gnomad EAS

AF:

0.123

Gnomad SAS

AF:

0.156

Gnomad FIN

AF:

0.127

Gnomad MID

AF:

0.0414

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.0831

GnomAD4 exome

AF:

0.0711

AC:

276

AN:

3880

Hom.:

Cov.:

AF XY:

0.0773

AC XY:

153

AN XY:

1980

show subpopulations

African (AFR)

AF:

0.0783

AC:

AN:

166

American (AMR)

AF:

0.0250

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00935

AC:

AN:

214

East Asian (EAS)

AF:

0.0708

AC:

AN:

212

South Asian (SAS)

AF:

0.0928

AC:

AN:

194

European-Finnish (FIN)

AF:

0.0658

AC:

AN:

152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0776

AC:

202

AN:

2604

Other (OTH)

AF:

0.0588

AC:

AN:

238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0985

AC:

14973

AN:

151982

Hom.:

788

Cov.:

AF XY:

0.0993

AC XY:

7381

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.0945

AC:

3919

AN:

41488

American (AMR)

AF:

0.0678

AC:

1036

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0314

AC:

109

AN:

3466

East Asian (EAS)

AF:

0.123

AC:

635

AN:

5150

South Asian (SAS)

AF:

0.156

AC:

749

AN:

4806

European-Finnish (FIN)

AF:

0.127

AC:

1340

AN:

10570

Middle Eastern (MID)

AF:

0.0479

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.102

AC:

6952

AN:

67916

Other (OTH)

AF:

0.0832

AC:

175

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

703

1406

2110

2813

3516

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:

0.0420

Hom.:

Bravo

AF:

0.0922

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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1-11805759-GC-GCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over