NM_000254.3:c.940G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000254.3(MTR):c.940G>A(p.Asp314Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0202 in 1,613,906 control chromosomes in the GnomAD database, including 448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 29 hom., cov: 32)

Exomes 𝑓: 0.020 ( 419 hom. )

Consequence

MTR
NM_000254.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.10

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

methylcobalamin deficiency type cblG
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P

MTR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009125441).

BP6

Variant 1-236826841-G-A is Benign according to our data. Variant chr1-236826841-G-A is described in ClinVar as Benign. ClinVar VariationId is 296556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0181 (2761/152262) while in subpopulation NFE AF = 0.0235 (1599/68024). AF 95% confidence interval is 0.0225. There are 29 homozygotes in GnomAd4. There are 1290 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3 link	c.940G>A	p.Asp314Asn	missense_variant	Exon 11 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.940G>A	p.Asp314Asn	missense_variant	Exon 11 of 33	1	NM_000254.3	ENSP00000355536.5		Q99707-1

Frequencies

GnomAD3 genomes

AF:

0.0182

AC:

2762

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00927

Gnomad AMI

AF:

0.0736

Gnomad AMR

AF:

0.0193

Gnomad ASJ

AF:

0.0507

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.0137

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0235

Gnomad OTH

AF:

0.0282

GnomAD2 exomes

AF:

0.0186

AC:

4682

AN:

251400

AF XY:

0.0185

show subpopulations

Gnomad AFR exome

AF:

0.00800

Gnomad AMR exome

AF:

0.0152

Gnomad ASJ exome

AF:

0.0491

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0158

Gnomad NFE exome

AF:

0.0255

Gnomad OTH exome

AF:

0.0233

GnomAD4 exome

AF:

0.0204

AC:

29802

AN:

1461644

Hom.:

419

Cov.:

AF XY:

0.0200

AC XY:

14518

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.00950

AC:

318

AN:

33480

American (AMR)

AF:

0.0163

AC:

731

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0529

AC:

1383

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39684

South Asian (SAS)

AF:

0.00546

AC:

471

AN:

86256

European-Finnish (FIN)

AF:

0.0145

AC:

777

AN:

53408

Middle Eastern (MID)

AF:

0.0444

AC:

256

AN:

5768

European-Non Finnish (NFE)

AF:

0.0221

AC:

24573

AN:

1111806

Other (OTH)

AF:

0.0214

AC:

1291

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

1445

2890

4335

5780

7225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

884

1768

2652

3536

4420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0181

AC:

2761

AN:

152262

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

1290

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00927

AC:

385

AN:

41548

American (AMR)

AF:

0.0193

AC:

295

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0507

AC:

176

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00394

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0137

AC:

145

AN:

10600

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0235

AC:

1599

AN:

68024

Other (OTH)

AF:

0.0279

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

134

268

402

536

670

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0223

Hom.:

162

Bravo

AF:

0.0187

TwinsUK

AF:

0.0245

AC:

ALSPAC

AF:

0.0218

AC:

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.0262

AC:

225

ExAC

AF:

0.0191

AC:

2317

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0258

EpiControl

AF:

0.0257

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 25, 2023

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

- -

not specified

Benign:1

Jan 29, 2016

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. -

Methylcobalamin deficiency type cblG

Benign:1

Feb 02, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

.;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.041

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.0091

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L

PhyloP100

4.1

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.5

D;N

REVEL

Benign

0.12

Sift

Benign

0.20

T;T

Sift4G

Benign

0.25

T;T

Polyphen

0.23

.;B

Vest4

0.18

MPC

0.43

ClinPred

0.025

GERP RS

3.1

Varity_R

0.12

gMVP

0.80

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over