1-236895528-C-T

Variant names:

• chr1-236895528-C-T
• rs1131449
• NM_000254.3:c.3576C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000254.3(MTR):​c.3576C>T​(p.Leu1192Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 1,580,542 control chromosomes in the GnomAD database, including 264,432 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1192L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.54 (22919 hom., cov: 31)
  • Exomes 𝑓: 0.58 (241513 hom.)
• Consequence: MTR NM_000254.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.37
• Publications: 25 publications found

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]

MTR Gene-Disease associations (from GenCC):

• methylcobalamin deficiency type cblG

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-236895528-C-T is Benign according to our data. Variant chr1-236895528-C-T is described in ClinVar as Benign. ClinVar VariationId is 138284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.3576C>T	p.Leu1192Leu	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.3576C>T	p.Leu1192Leu	synonymous_variant	Exon 31 of 33	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.2238C>T	p.Leu746Leu	synonymous_variant	Exon 18 of 20	1		ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.544 AC: 82672 AN: 151864 Hom.: 22891 Cov.: 31

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.743

Gnomad AMR AF: 0.560

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.552

Gnomad SAS AF: 0.606

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.510

GnomAD2 exomes AF: 0.576 AC: 113625 AN: 197208 AF XY: 0.577

Gnomad AFR exome AF: 0.461

Gnomad AMR exome AF: 0.615

Gnomad ASJ exome AF: 0.467

Gnomad EAS exome AF: 0.543

Gnomad FIN exome AF: 0.630

Gnomad NFE exome AF: 0.572

Gnomad OTH exome AF: 0.569

GnomAD4 exome AF: 0.580 AC: 828591 AN: 1428560 Hom.: 241513 Cov.: 65 AF XY: 0.581 AC XY: 411013 AN XY: 707452

African (AFR) AF: 0.457 AC: 14938 AN: 32674

American (AMR) AF: 0.610 AC: 25014 AN: 41010

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 12014 AN: 25502

East Asian (EAS) AF: 0.601 AC: 22811 AN: 37926

South Asian (SAS) AF: 0.619 AC: 50496 AN: 81602

European-Finnish (FIN) AF: 0.632 AC: 32293 AN: 51058

Middle Eastern (MID) AF: 0.482 AC: 2760 AN: 5730

European-Non Finnish (NFE) AF: 0.581 AC: 635152 AN: 1094016

Other (OTH) AF: 0.561 AC: 33113 AN: 59042

GnomAD4 genome AF: 0.544 AC: 82742 AN: 151982 Hom.: 22919 Cov.: 31 AF XY: 0.549 AC XY: 40743 AN XY: 74268

African (AFR) AF: 0.456 AC: 18915 AN: 41450

American (AMR) AF: 0.561 AC: 8576 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 1631 AN: 3472

East Asian (EAS) AF: 0.553 AC: 2840 AN: 5140

South Asian (SAS) AF: 0.606 AC: 2916 AN: 4810

European-Finnish (FIN) AF: 0.631 AC: 6656 AN: 10556

Middle Eastern (MID) AF: 0.483 AC: 141 AN: 292

European-Non Finnish (NFE) AF: 0.578 AC: 39309 AN: 67962

Other (OTH) AF: 0.514 AC: 1082 AN: 2104

Alfa AF: 0.558 Hom.: 30316

Bravo AF: 0.534

Asia WGS AF: 0.572 AC: 1989 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 09, 2013

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Methylcobalamin deficiency type cblG Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

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	-0.76
CADD	Benign	0.049
DANN	Benign	0.55
PhyloP100		-3.4
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1131449; hg19: chr1-237058828; COSMIC: COSV63964165;