rs2229276

Positions:

• chr1-236891269-A-G
• chr1-236891269-A-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.3144A>G​(p.Ala1048=) 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 (★★).

• 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

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=-0.88).
• BP6: Variant 1-236891269-A-G is Benign according to our data. Variant chr1-236891269-A-G is described in ClinVar as [Benign]. Clinvar id is 138290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236891269-A-G is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTR	NM_000254.3	c.3144A>G	p.Ala1048=	synonymous_variant	29/33	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.3144A>G	p.Ala1048=	synonymous_variant	29/33	1	NM_000254.3	ENSP00000355536	P1

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

GnomAD3 exomes AF: 0.390 AC: 97975 AN: 251450 Hom.: 19857 AF XY: 0.386 AC XY: 52402 AN XY: 135896

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 SAS exome AF: 0.321

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

Gnomad4 AFR exome AF: 0.188

Gnomad4 AMR exome AF: 0.448

Gnomad4 ASJ exome AF: 0.328

Gnomad4 EAS exome AF: 0.464

Gnomad4 SAS exome AF: 0.322

Gnomad4 FIN exome AF: 0.443

Gnomad4 NFE exome AF: 0.408

Gnomad4 OTH exome AF: 0.376

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

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.402

Gnomad4 ASJ AF: 0.322

Gnomad4 EAS AF: 0.442

Gnomad4 SAS AF: 0.304

Gnomad4 FIN AF: 0.446

Gnomad4 NFE AF: 0.407

Gnomad4 OTH AF: 0.340

Alfa AF: 0.386 Hom.: 10096

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

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. -
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	-	- -

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	-0.88
CADD	Benign	0.078
DANN	Benign	0.35

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: rs2229276; hg19: chr1-237054569; COSMIC: COSV63966508; COSMIC: COSV63966508;