1-236895448-C-T

Variant names:

• chr1-236895448-C-T
• rs12030699
• NM_000254.3:c.3496C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000254.3(MTR):​c.3496C>T​(p.Leu1166Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0067 in 1,601,094 control chromosomes in the GnomAD database, including 855 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (134 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (721 hom.)
• Consequence: MTR NM_000254.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.07

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 1-236895448-C-T is Benign according to our data. Variant chr1-236895448-C-T is described in ClinVar as [Benign]. Clinvar id is 296579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.3496C>T	p.Leu1166Leu	synonymous_variant	Exon 31 of 33	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.3496C>T	p.Leu1166Leu	synonymous_variant	Exon 31 of 33	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.2158C>T	p.Leu720Leu	synonymous_variant	Exon 18 of 20	1		ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.00906 AC: 1378 AN: 152168 Hom.: 136 Cov.: 33

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00536

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.0189 AC: 4295 AN: 227274 Hom.: 412 AF XY: 0.0183 AC XY: 2249 AN XY: 122672

Gnomad AFR exome AF: 0.00217

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.00223

Gnomad EAS exome AF: 0.213

Gnomad SAS exome AF: 0.0134

Gnomad FIN exome AF: 0.000360

Gnomad NFE exome AF: 0.000425

Gnomad OTH exome AF: 0.0102

GnomAD4 exome AF: 0.00646 AC: 9358 AN: 1448808 Hom.: 721 Cov.: 60 AF XY: 0.00659 AC XY: 4740 AN XY: 719214

Gnomad4 AFR exome AF: 0.00171

Gnomad4 AMR exome AF: 0.00387

Gnomad4 ASJ exome AF: 0.00245

Gnomad4 EAS exome AF: 0.178

Gnomad4 SAS exome AF: 0.0128

Gnomad4 FIN exome AF: 0.000497

Gnomad4 NFE exome AF: 0.000194

Gnomad4 OTH exome AF: 0.0128

GnomAD4 genome AF: 0.00901 AC: 1372 AN: 152286 Hom.: 134 Cov.: 33 AF XY: 0.00991 AC XY: 738 AN XY: 74440

Gnomad4 AFR AF: 0.00207

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.204

Gnomad4 SAS AF: 0.0209

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.000961 Hom.: 2

Bravo AF: 0.0109

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jun 01, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Methylcobalamin deficiency type cblG Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Disorders of Intracellular Cobalamin Metabolism Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	10
DANN	Benign	0.74

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: rs12030699; hg19: chr1-237058748; COSMIC: COSV63965267;