1-236874861-T-C

Variant names:

• chr1-236874861-T-C
• rs1770449
• NM_000254.3:c.2594+15T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000254.3(MTR):​c.2594+15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 1,611,418 control chromosomes in the GnomAD database, including 99,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7105 hom., cov: 32)
  • Exomes 𝑓: 0.35 (92293 hom.)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.157
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-236874861-T-C is Benign according to our data. Variant chr1-236874861-T-C is described in ClinVar as Benign. ClinVar VariationId is 138288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.2594+15T>C		intron_variant	Intron 24 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.2594+15T>C		intron_variant	Intron 24 of 32	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.1256+15T>C		intron_variant	Intron 11 of 19	1		ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41912 AN: 152062 Hom.: 7111 Cov.: 32

Gnomad AFR AF: 0.0817

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.466

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.314

GnomAD2 exomes AF: 0.322 AC: 80647 AN: 250476 AF XY: 0.328

Gnomad AFR exome AF: 0.0701

Gnomad AMR exome AF: 0.313

Gnomad ASJ exome AF: 0.463

Gnomad EAS exome AF: 0.192

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.375

Gnomad OTH exome AF: 0.344

GnomAD4 exome AF: 0.349 AC: 509353 AN: 1459238 Hom.: 92293 Cov.: 34 AF XY: 0.348 AC XY: 252911 AN XY: 725980

African (AFR) AF: 0.0649 AC: 2170 AN: 33426

American (AMR) AF: 0.311 AC: 13883 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 11996 AN: 26100

East Asian (EAS) AF: 0.161 AC: 6379 AN: 39592

South Asian (SAS) AF: 0.280 AC: 24110 AN: 86182

European-Finnish (FIN) AF: 0.343 AC: 18255 AN: 53298

Middle Eastern (MID) AF: 0.373 AC: 2152 AN: 5762

European-Non Finnish (NFE) AF: 0.369 AC: 409858 AN: 1109912

Other (OTH) AF: 0.341 AC: 20550 AN: 60278

GnomAD4 genome AF: 0.275 AC: 41900 AN: 152180 Hom.: 7105 Cov.: 32 AF XY: 0.274 AC XY: 20417 AN XY: 74396

African (AFR) AF: 0.0815 AC: 3388 AN: 41568

American (AMR) AF: 0.323 AC: 4934 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 1617 AN: 3468

East Asian (EAS) AF: 0.187 AC: 967 AN: 5170

South Asian (SAS) AF: 0.273 AC: 1319 AN: 4826

European-Finnish (FIN) AF: 0.348 AC: 3677 AN: 10580

Middle Eastern (MID) AF: 0.363 AC: 106 AN: 292

European-Non Finnish (NFE) AF: 0.369 AC: 25050 AN: 67962

Other (OTH) AF: 0.311 AC: 657 AN: 2112

Alfa AF: 0.306 Hom.: 6544

Bravo AF: 0.264

Asia WGS AF: 0.228 AC: 795 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 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. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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	-0.83
CADD	Benign	1.9
DANN	Benign	0.52
PhyloP100		-0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs1770449; hg19: chr1-237038161; COSMIC: COSV63964725;