Genetic Variant NM_005957.5:c.1056C>A (chr1-11794839-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_005957.5(MTHFR):c.1056C>A(p.Ser352Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S352S) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

MTHFR
NM_005957.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.561

Publications

43 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: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_005957.5

PM2

Very rare variant in population databases, with high coverage;

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
MTHFR	NM_005957.5	MANE Select	c.1056C>A	p.Ser352Arg	missense	Exon 7 of 12	NP_005948.3
MTHFR	NM_001330358.2		c.1179C>A	p.Ser393Arg	missense	Exon 7 of 12	NP_001317287.1
MTHFR	NM_001410750.1		c.1176C>A	p.Ser392Arg	missense	Exon 7 of 12	NP_001397679.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.1056C>A	p.Ser352Arg	missense	Exon 7 of 12	ENSP00000365775.3
MTHFR	ENST00000423400.7	TSL:1	c.1176C>A	p.Ser392Arg	missense	Exon 7 of 12	ENSP00000398908.3
MTHFR	ENST00000376592.6	TSL:1	c.1056C>A	p.Ser352Arg	missense	Exon 7 of 12	ENSP00000365777.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

329

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.35

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.47

MetaRNN

Uncertain

0.70

MetaSVM

Uncertain

-0.12

MutationAssessor

Pathogenic

3.2

PhyloP100

-0.56

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.57

Sift

Uncertain

0.021

Sift4G

Uncertain

0.020

Polyphen

0.68

Vest4

0.81

MutPred

0.37

Gain of MoRF binding (P = 0.0105)

MVP

0.64

MPC

0.96

ClinPred

0.86

GERP RS

-5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.89

gMVP

0.95

Mutation Taster

=28/72

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over