1-236891269-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.12

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 -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 rank	MANE	Protein	UniProt
MTR	NM_000254.3 link	c.3144A>G	p.Ala1048Ala	synonymous_variant	Exon 29 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.3144A>G	p.Ala1048Ala	synonymous_variant	Exon 29 of 33	1	NM_000254.3	ENSP00000355536.5		Q99707-1
MTR	ENST00000366576.3 link	c.1806A>G	p.Ala602Ala	synonymous_variant	Exon 16 of 20	1		ENSP00000355535.3		B1ANE3

Frequencies

GnomAD3 genomes

AF:

0.347

AC:

52763

AN:

151922

Hom.:

9993

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.397

AC XY:

288518

AN XY:

727194

show subpopulations

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.:

AF XY:

0.349

AC XY:

25935

AN XY:

74292

show subpopulations

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

LINK: link

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

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

-0.88

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

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