1-236895528-C-T

Position:

• chr1-236895528-C-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.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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 138284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236895528-C-T is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
MTR	NM_000254.3	c.3576C>T	p.Leu1192Leu	synonymous_variant	31/33	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.3576C>T	p.Leu1192Leu	synonymous_variant	31/33	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.2238C>T	p.Leu746Leu	synonymous_variant	18/20	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

GnomAD3 exomes AF: 0.576 AC: 113625 AN: 197208 Hom.: 32813 AF XY: 0.577 AC XY: 60967 AN XY: 105676

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 SAS exome AF: 0.620

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

Gnomad4 AFR exome AF: 0.457

Gnomad4 AMR exome AF: 0.610

Gnomad4 ASJ exome AF: 0.471

Gnomad4 EAS exome AF: 0.601

Gnomad4 SAS exome AF: 0.619

Gnomad4 FIN exome AF: 0.632

Gnomad4 NFE exome AF: 0.581

Gnomad4 OTH exome AF: 0.561

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

Gnomad4 AFR AF: 0.456

Gnomad4 AMR AF: 0.561

Gnomad4 ASJ AF: 0.470

Gnomad4 EAS AF: 0.553

Gnomad4 SAS AF: 0.606

Gnomad4 FIN AF: 0.631

Gnomad4 NFE AF: 0.578

Gnomad4 OTH AF: 0.514

Alfa AF: 0.563 Hom.: 22620

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

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2013	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:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Disorders of Intracellular Cobalamin Metabolism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.049
DANN	Benign	0.55

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