1-236891269-A-G

Variant names:

• chr1-236891269-A-G
• rs2229276
• NM_000254.3:c.3144A>G

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.3144A>G​(p.Ala1048Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 1,613,820 control chromosomes in the GnomAD database, including 128,404 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. A1048A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.35 (9997 hom., cov: 32)
  • Exomes 𝑓: 0.40 (118407 hom.)
• Consequence: MTR NM_000254.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.12
• Publications: 29 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=-0.88).
• BP6: Variant 1-236891269-A-G is Benign according to our data. Variant chr1-236891269-A-G is described in ClinVar as Benign. ClinVar VariationId is 138290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000254.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	NM_000254.3	MANE Select	c.3144A>G	p.Ala1048Ala	synonymous	Exon 29 of 33	NP_000245.2
	MTR	NM_001291939.1		c.2991A>G	p.Ala997Ala	synonymous	Exon 28 of 32	NP_001278868.1
	MTR	NM_001410942.1		c.2955A>G	p.Ala985Ala	synonymous	Exon 27 of 31	NP_001397871.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	ENST00000366577.10	TSL:1 MANE Select	c.3144A>G	p.Ala1048Ala	synonymous	Exon 29 of 33	ENSP00000355536.5
	MTR	ENST00000535889.6	TSL:1	c.2991A>G	p.Ala997Ala	synonymous	Exon 28 of 32	ENSP00000441845.1
	MTR	ENST00000366576.3	TSL:1	c.1806A>G	p.Ala602Ala	synonymous	Exon 16 of 20	ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52763 AN: 151922 Hom.: 9993 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.344

GnomAD2 exomes AF: 0.390 AC: 97975 AN: 251450 AF XY: 0.386

Gnomad AFR exome AF: 0.194

Gnomad AMR exome AF: 0.447

Gnomad ASJ exome AF: 0.332

Gnomad EAS exome AF: 0.443

Gnomad FIN exome AF: 0.443

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.394

GnomAD4 exome AF: 0.399 AC: 583405 AN: 1461778 Hom.: 118407 Cov.: 56 AF XY: 0.397 AC XY: 288518 AN XY: 727194

African (AFR) AF: 0.188 AC: 6299 AN: 33476

American (AMR) AF: 0.448 AC: 20034 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 8561 AN: 26136

East Asian (EAS) AF: 0.464 AC: 18424 AN: 39698

South Asian (SAS) AF: 0.322 AC: 27802 AN: 86254

European-Finnish (FIN) AF: 0.443 AC: 23638 AN: 53418

Middle Eastern (MID) AF: 0.301 AC: 1733 AN: 5760

European-Non Finnish (NFE) AF: 0.408 AC: 454205 AN: 1111924

Other (OTH) AF: 0.376 AC: 22709 AN: 60388

GnomAD4 genome AF: 0.347 AC: 52792 AN: 152042 Hom.: 9997 Cov.: 32 AF XY: 0.349 AC XY: 25935 AN XY: 74292

African (AFR) AF: 0.196 AC: 8112 AN: 41484

American (AMR) AF: 0.402 AC: 6137 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1119 AN: 3470

East Asian (EAS) AF: 0.442 AC: 2283 AN: 5162

South Asian (SAS) AF: 0.304 AC: 1466 AN: 4816

European-Finnish (FIN) AF: 0.446 AC: 4707 AN: 10564

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.407 AC: 27628 AN: 67958

Other (OTH) AF: 0.340 AC: 718 AN: 2112

Alfa AF: 0.379 Hom.: 13150

Bravo AF: 0.342

Asia WGS AF: 0.363 AC: 1262 AN: 3478

EpiCase AF: 0.404

EpiControl AF: 0.395

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Methylcobalamin deficiency type cblG Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.078
DANN	Benign	0.35
PhyloP100		-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: rs2229276; hg19: chr1-237054569; COSMIC: COSV63966508; COSMIC: COSV63966508;