rs786204013

Positions:

• chr1-11801196-T-A
• chr1-11801196-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_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. 12/21 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0130

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 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 id is 187875.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24342161).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFR	NM_005957.5	c.440A>T	p.Gln147Leu	missense_variant	3/12	ENST00000376590.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9	c.440A>T	p.Gln147Leu	missense_variant	3/12	1	NM_005957.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.86	D;.;.;D;.;.;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.95	.;D;.;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.6	L;.;.;L;.;.;.
MutationTaster	Benign	0.85	D;D;D;D
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.0	D;D;D;D;.;.;.
REVEL	Benign	0.23
Sift	Benign	0.18	T;T;T;T;.;.;.
Sift4G	Benign	0.21	T;T;T;T;.;.;.
Polyphen		0.0010	B;.;.;B;.;.;.
Vest4		0.24
MutPred		0.47		Loss of disorder (P = 0.0409);.;.;Loss of disorder (P = 0.0409);.;Loss of disorder (P = 0.0409);Loss of disorder (P = 0.0409);
MVP		0.87
MPC		0.29
ClinPred		0.44	T
GERP RS		1.4
Varity_R		0.32
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs786204013; hg19: chr1-11861253;