NM_000254.3:c.2756A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000254.3(MTR):c.2756A>G(p.Asp919Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,590,910 control chromosomes in the GnomAD database, including 34,048 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3656 hom., cov: 32)

Exomes 𝑓: 0.20 ( 30392 hom. )

Consequence

MTR
NM_000254.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:7O:1

Conservation

PhyloP100: 8.54

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016700923).

BP6

Variant 1-236885200-A-G is Benign according to our data. Variant chr1-236885200-A-G is described in ClinVar as [Benign]. Clinvar id is 138289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236885200-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3 link	c.2756A>G	p.Asp919Gly	missense_variant	Exon 26 of 33	ENST00000366577.10	NP_000245.2	Q99707-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10 link	c.2756A>G	p.Asp919Gly	missense_variant	Exon 26 of 33	1	NM_000254.3	ENSP00000355536.5		Q99707-1
MTR	ENST00000366576.3 link	c.1418A>G	p.Asp473Gly	missense_variant	Exon 13 of 20	1		ENSP00000355535.3		B1ANE3

Frequencies

GnomAD3 genomes

AF:

0.213

AC:

32337

AN:

152018

Hom.:

3645

Cov.:

show subpopulations

Gnomad AFR

AF:

0.263

Gnomad AMI

AF:

0.190

Gnomad AMR

AF:

0.184

Gnomad ASJ

AF:

0.175

Gnomad EAS

AF:

0.122

Gnomad SAS

AF:

0.313

Gnomad FIN

AF:

0.189

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.196

Gnomad OTH

AF:

0.188

GnomAD3 exomes

AF:

0.203

AC:

50989

AN:

251124

Hom.:

5663

AF XY:

0.208

AC XY:

28257

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.266

Gnomad AMR exome

AF:

0.184

Gnomad ASJ exome

AF:

0.168

Gnomad EAS exome

AF:

0.111

Gnomad SAS exome

AF:

0.311

Gnomad FIN exome

AF:

0.192

Gnomad NFE exome

AF:

0.191

Gnomad OTH exome

AF:

0.197

GnomAD4 exome

AF:

0.200

AC:

287192

AN:

1438774

Hom.:

30392

Cov.:

AF XY:

0.203

AC XY:

145505

AN XY:

717146

show subpopulations

Gnomad4 AFR exome

AF:

0.268

Gnomad4 AMR exome

AF:

0.182

Gnomad4 ASJ exome

AF:

0.172

Gnomad4 EAS exome

AF:

0.151

Gnomad4 SAS exome

AF:

0.307

Gnomad4 FIN exome

AF:

0.197

Gnomad4 NFE exome

AF:

0.192

Gnomad4 OTH exome

AF:

0.203

GnomAD4 genome

AF:

0.213

AC:

32375

AN:

152136

Hom.:

3656

Cov.:

AF XY:

0.214

AC XY:

15932

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.263

Gnomad4 AMR

AF:

0.184

Gnomad4 ASJ

AF:

0.175

Gnomad4 EAS

AF:

0.121

Gnomad4 SAS

AF:

0.311

Gnomad4 FIN

AF:

0.189

Gnomad4 NFE

AF:

0.196

Gnomad4 OTH

AF:

0.196

Alfa

AF:

0.192

Hom.:

7497

Bravo

AF:

0.209

TwinsUK

AF:

0.203

AC:

752

ALSPAC

AF:

0.199

AC:

768

ESP6500AA

AF:

0.264

AC:

1164

ESP6500EA

AF:

0.198

AC:

1702

ExAC

AF:

0.209

AC:

25325

Asia WGS

AF:

0.218

AC:

758

AN:

3478

EpiCase

AF:

0.182

EpiControl

AF:

0.182

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

not provided

Benign:2

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Gastrointestinal stromal tumor

Uncertain:1

Department of Pharmacy and Biotechnology, University of Bologna

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: case-control

- -

not specified

Benign:1

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. -

Disorders of Intracellular Cobalamin Metabolism

Benign:1

Mar 06, 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. -

MTR-related disorder

Benign:1

Jul 29, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Neural tube defects, folate-sensitive, susceptibility to

Other:1

Sep 01, 2003

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.61

.;D;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.76

T;T;T

MetaRNN

Benign

0.0017

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

.;L;.

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Uncertain

0.34

Sift

Benign

0.19

T;T;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.16

.;B;.

Vest4

0.22

MPC

0.70

ClinPred

0.040

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.58

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over