rs786204024

Positions:

• chr1-11794781-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_005957.5(MTHFR):​c.1114A>G​(p.Lys372Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.50

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-11794781-T-C is Pathogenic according to our data. Variant chr1-11794781-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 187890.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFR	NM_005957.5	c.1114A>G	p.Lys372Glu	missense_variant	7/12	ENST00000376590.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9	c.1114A>G	p.Lys372Glu	missense_variant	7/12	1	NM_005957.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

University Children's Hospital, University of Zurich

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.;.;D;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	.;D;.;D;D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.046	T
MutationAssessor	Uncertain	2.2	M;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.1	D;D;D;D;.;.;.
REVEL	Pathogenic	0.69
Sift	Benign	0.036	D;T;T;D;.;.;.
Sift4G	Uncertain	0.044	D;D;D;D;.;.;.
Polyphen		0.048	B;.;.;B;.;.;.
Vest4		0.89
MutPred		0.36		Loss of MoRF binding (P = 0.0038);.;.;Loss of MoRF binding (P = 0.0038);.;Loss of MoRF binding (P = 0.0038);.;
MVP		0.72
MPC		0.38
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.74
gMVP		0.86

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

Other links and lift over

dbSNP: rs786204024; hg19: chr1-11854838;