rs11799647

chr1-236897621-A-Cchr1-236897621-A-Gchr1-236897621-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000254.3(MTR):c.3775A>C(p.Ile1259Leu) variant causes a missense change. 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTR NM_000254.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.87

Genes affected

MTR (HGNC:7468): (5-methyltetrahydrofolate-homocysteine methyltransferase) This gene encodes the 5-methyltetrahydrofolate-homocysteine methyltransferase. This enzyme, also known as cobalamin-dependent methionine synthase, catalyzes the final step in methionine biosynthesis. Mutations in MTR have been identified as the underlying cause of methylcobalamin deficiency complementation group G. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MTR
• BP4: Computational evidence support a benign effect (MetaRNN=0.31325254).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTR	NM_000254.3	c.3775A>C	p.Ile1259Leu	missense_variant	33/33	ENST00000366577.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTR	ENST00000366577.10	c.3775A>C	p.Ile1259Leu	missense_variant	33/33	1	NM_000254.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	21
Dann	Benign	0.92
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.0090
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.35	T;T;T
Sift4G	Benign	0.65	T;T;T
Polyphen		0.044	.;B;.
Vest4		0.47
MutPred		0.41		.;Loss of methylation at K1254 (P = 0.0488);.;
MVP		0.68
MPC		0.45
ClinPred		0.61	D
GERP RS		3.9
Varity_R		0.30
gMVP		0.68

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: rs11799647; hg19: chr1-237060921;