Variant chr1-11802980-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

The NM_005957.5(MTHFR):c.137G>C(p.Arg46Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R46W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MTHFR
NM_005957.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.45

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-11802981-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFR	NM_005957.5 linkuse as main transcript	c.137G>C	p.Arg46Pro	missense_variant	2/12	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9 linkuse as main transcript	c.137G>C	p.Arg46Pro	missense_variant	2/12	1	NM_005957.5	ENSP00000365775	A1	P42898-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251332

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.;.;T;.;.;.;.

Eigen

Benign

0.14

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.94

.;D;.;D;D;D;D;D

M_CAP

Benign

0.075

MetaRNN

Uncertain

0.52

D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.40

MutationAssessor

Uncertain

2.5

M;.;.;M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.81

N;N;N;N;.;.;.;N

REVEL

Uncertain

0.51

Sift

Benign

0.31

T;T;T;T;.;.;.;T

Sift4G

Benign

0.29

T;T;T;T;.;.;.;.

Polyphen

0.80

P;.;.;P;.;.;.;.

Vest4

0.53

MutPred

0.39

Loss of MoRF binding (P = 0.015);.;.;Loss of MoRF binding (P = 0.015);.;Loss of MoRF binding (P = 0.015);Loss of MoRF binding (P = 0.015);Loss of MoRF binding (P = 0.015);

MVP

0.93

MPC

0.64

ClinPred

0.78

GERP RS

2.8

Varity_R

0.59

gMVP

0.93

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over