1-11801299-C-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_005957.5(MTHFR):c.337G>C(p.Ala113Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A113T) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

MTHFR
NM_005957.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.25

Publications

9 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-11801299-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 187872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTHFR	NM_005957.5	MANE Select	c.337G>C	p.Ala113Pro	missense	Exon 3 of 12	NP_005948.3
MTHFR	NM_001330358.2		c.460G>C	p.Ala154Pro	missense	Exon 3 of 12	NP_001317287.1	P42898-2
MTHFR	NM_001410750.1		c.457G>C	p.Ala153Pro	missense	Exon 3 of 12	NP_001397679.1	Q5SNW7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.337G>C	p.Ala113Pro	missense	Exon 3 of 12	ENSP00000365775.3	P42898-1
MTHFR	ENST00000423400.7	TSL:1	c.457G>C	p.Ala153Pro	missense	Exon 3 of 12	ENSP00000398908.3	Q5SNW7
MTHFR	ENST00000376592.6	TSL:1	c.337G>C	p.Ala113Pro	missense	Exon 3 of 12	ENSP00000365777.1	P42898-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

PhyloP100

7.3

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.026

Polyphen

0.98

Vest4

0.97

MutPred

0.76

Loss of helix (P = 0.0237)

MVP

1.0

MPC

1.1

ClinPred

1.0

GERP RS

5.7

Varity_R

0.98

gMVP

0.99

Mutation Taster

=3/97

disease causing

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over