chr1-236897621-A-T

Variant names:

• chr1-236897621-A-T
• rs11799647
• NM_000254.3:c.3775A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000254.3(MTR):​c.3775A>T​(p.Ile1259Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Failed GnomAD Quality Control
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.3775A>T	p.Ile1259Phe	missense_variant	Exon 33 of 33	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.3775A>T	p.Ile1259Phe	missense_variant	Exon 33 of 33	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.2437A>T	p.Ile813Phe	missense_variant	Exon 20 of 20	1		ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 149652 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 149652 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72884

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.63	.;D;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.50	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	3.4	.;M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Uncertain	0.51
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.70	T;T;T
Polyphen		0.91	.;P;.
Vest4		0.57
MutPred		0.43		.;Gain of relative solvent accessibility (P = 0.09);.;
MVP		0.85
MPC		1.2
ClinPred		0.87	D
GERP RS		3.9
Varity_R		0.48
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;