Genetic Variant NM_005957.5:c.440A>T (chr1-11801196-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_005957.5(MTHFR):c.440A>T(p.Gln147Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. Q147P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

MTHFR
NM_005957.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0130

Publications

5 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-11801196-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 187875.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.24342161).

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.440A>T	p.Gln147Leu	missense	Exon 3 of 12	NP_005948.3
MTHFR	NM_001330358.2		c.563A>T	p.Gln188Leu	missense	Exon 3 of 12	NP_001317287.1
MTHFR	NM_001410750.1		c.560A>T	p.Gln187Leu	missense	Exon 3 of 12	NP_001397679.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.440A>T	p.Gln147Leu	missense	Exon 3 of 12	ENSP00000365775.3
MTHFR	ENST00000423400.7	TSL:1	c.560A>T	p.Gln187Leu	missense	Exon 3 of 12	ENSP00000398908.3
MTHFR	ENST00000376592.6	TSL:1	c.440A>T	p.Gln147Leu	missense	Exon 3 of 12	ENSP00000365777.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.86

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.29

MutationAssessor

Benign

1.6

PhyloP100

0.013

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.23

Sift

Benign

0.18

Sift4G

Benign

0.21

Polyphen

0.0010

Vest4

0.24

MutPred

0.47

Loss of disorder (P = 0.0409)

MVP

0.87

MPC

0.29

ClinPred

0.44

GERP RS

1.4

Varity_R

0.32

gMVP

0.70

Mutation Taster

=24/76

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over