dbSNP rs45594036: MTHFR:c.-14+128G>T (chr1-11805760-C-A) – 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.-14+128G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0453 in 128,344 control chromosomes in the GnomAD database, including 159 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 0.045 ( 151 hom., cov: 31)

Exomes 𝑓: 0.043 ( 8 hom. )

Consequence

MTHFR
NM_005957.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.03

Publications

4 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=-0.72).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.065 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5 link	c.-14+128G>T		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+128G>T		intron_variant	Intron 1 of 11	1	NM_005957.5	ENSP00000365775.3		P42898-1

Frequencies

GnomAD3 genomes

AF:

0.0454

AC:

5636

AN:

124152

Hom.:

149

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0134

Gnomad AMI

AF:

0.0400

Gnomad AMR

AF:

0.0463

Gnomad ASJ

AF:

0.0576

Gnomad EAS

AF:

0.00276

Gnomad SAS

AF:

0.0578

Gnomad FIN

AF:

0.0417

Gnomad MID

AF:

0.0822

Gnomad NFE

AF:

0.0668

Gnomad OTH

AF:

0.0493

GnomAD4 exome

AF:

0.0434

AC:

177

AN:

4076

Hom.:

Cov.:

AF XY:

0.0459

AC XY:

AN XY:

2092

show subpopulations

African (AFR)

AF:

0.00575

AC:

AN:

174

American (AMR)

AF:

0.0349

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.0474

AC:

AN:

232

East Asian (EAS)

AF:

0.00

AC:

AN:

220

South Asian (SAS)

AF:

0.0153

AC:

AN:

196

European-Finnish (FIN)

AF:

0.0208

AC:

AN:

144

Middle Eastern (MID)

AF:

0.0385

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0527

AC:

145

AN:

2750

Other (OTH)

AF:

0.0403

AC:

AN:

248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.0454

AC:

5641

AN:

124268

Hom.:

151

Cov.:

AF XY:

0.0455

AC XY:

2763

AN XY:

60682

show subpopulations

African (AFR)

AF:

0.0133

AC:

455

AN:

34104

American (AMR)

AF:

0.0462

AC:

617

AN:

13348

Ashkenazi Jewish (ASJ)

AF:

0.0576

AC:

188

AN:

3264

East Asian (EAS)

AF:

0.00276

AC:

AN:

3980

South Asian (SAS)

AF:

0.0576

AC:

202

AN:

3504

European-Finnish (FIN)

AF:

0.0417

AC:

337

AN:

8084

Middle Eastern (MID)

AF:

0.0858

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.0668

AC:

3680

AN:

55106

Other (OTH)

AF:

0.0533

AC:

AN:

1784

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

268

536

803

1071

1339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0445

Hom.:

Bravo

AF:

0.0363

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

7.2

(source)

DANN

Benign

0.83

PhyloP100

1.0

PromoterAI

-0.020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Mutation Taster

=100/0

polymorphism

(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