rs267606886

Variant names:

• chr1-11795114-A-C
• rs267606886
• NM_005957.5:c.1015T>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PP3 PP5_Very_Strong

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 (★★). ClinVar reports functional evidence for this variant: "SCV002242985: Experimental studies have shown that this variant affects MTHFR protein function (PMID:27743313)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.66
• Publications: 8 publications found

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)

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002242985: Experimental studies have shown that this variant affects MTHFR protein function (PMID: 27743313).; SCV005883667: The most pronounced variant effect results in <10% of normal enzyme activity (e.g. Burda_2015, Kluijtmans_1998). PMID: 25736335, 9781030
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_005957.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-11795114-A-C is Pathogenic according to our data. Variant chr1-11795114-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 3523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	NM_005957.5	MANE Select	c.1015T>G	p.Trp339Gly	missense	Exon 6 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.1138T>G	p.Trp380Gly	missense	Exon 6 of 12	NP_001317287.1	P42898-2
	MTHFR	NM_001410750.1		c.1135T>G	p.Trp379Gly	missense	Exon 6 of 12	NP_001397679.1	Q5SNW7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.1015T>G	p.Trp339Gly	missense	Exon 6 of 12	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000423400.7	TSL:1	c.1135T>G	p.Trp379Gly	missense	Exon 6 of 12	ENSP00000398908.3	Q5SNW7
	MTHFR	ENST00000376592.6	TSL:1	c.1015T>G	p.Trp339Gly	missense	Exon 6 of 12	ENSP00000365777.1	P42898-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Homocystinuria due to methylene tetrahydrofolate reductase deficiency (3)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		8.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.047	D
Polyphen		0.0060	B
Vest4		0.92
MutPred		0.86		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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267606886; hg19: chr1-11855171;