rs267606886

Positions:

• chr1-11795114-A-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_005957.5(MTHFR):​c.1015T>G​(p.Trp339Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.66

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_005957.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 1-11795114-A-C is Pathogenic according to our data. Variant chr1-11795114-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 3523.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.1015T>G	p.Trp339Gly	missense_variant	6/12	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9	c.1015T>G	p.Trp339Gly	missense_variant	6/12	1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 02, 2021	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects MTHFR protein function (PMID: 27743313). This variant has been observed in individual(s) with MTHFR deficiency (PMID: 9781030, 25736335). ClinVar contains an entry for this variant (Variation ID: 3523). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with glycine at codon 339 of the MTHFR protein (p.Trp339Gly). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and glycine. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1998	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	34
DANN	Benign	0.97
DEOGEN2	Uncertain	0.71	D;.;.;D;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D;.;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.9	M;.;.;M;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.2	D;D;D;D;.;.;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.027	D;T;T;D;.;.;.
Sift4G	Uncertain	0.047	D;T;T;D;.;.;.
Polyphen		0.0060	B;.;.;B;.;.;.
Vest4		0.92
MutPred		0.86		Gain of disorder (P = 0.0019);.;.;Gain of disorder (P = 0.0019);.;Gain of disorder (P = 0.0019);.;
MVP		0.97
MPC		1.2
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.83
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.59		Position offset: 22

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

Publications

LitVar

Other links and lift over

dbSNP: rs267606886; hg19: chr1-11855171;