rs162036

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002454.3(MTRR):c.1049A>G(p.Lys350Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,613,752 control chromosomes in the GnomAD database, including 20,669 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 4532 hom., cov: 31)

Exomes 𝑓: 0.13 ( 16137 hom. )

Consequence

MTRR
NM_002454.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:8

Conservation

PhyloP100: 1.22

Publications

81 publications found

Variant links:

Genes affected

MTRR (HGNC:7473): (5-methyltetrahydrofolate-homocysteine methyltransferase reductase) This gene encodes a member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases. This protein functions in the synthesis of methionine by regenerating methionine synthase to a functional state. Because methionine synthesis requires methyl-group transfer by a folate donor, activity of the encoded enzyme is important for folate metabolism and cellular methylation. Mutations in this gene can cause homocystinuria-megaloblastic anemia, cbl E type. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2015]

MTRR Gene-Disease associations (from GenCC):

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

MTRR 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=0.0026747882).

BP6

Variant 5-7885846-A-G is Benign according to our data. Variant chr5-7885846-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRR	NM_002454.3 link	c.1049A>G	p.Lys350Arg	missense_variant	Exon 7 of 15	ENST00000440940.7	NP_002445.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTRR	ENST00000440940.7 link	c.1049A>G	p.Lys350Arg	missense_variant	Exon 7 of 15	1	NM_002454.3	ENSP00000402510.2

Frequencies

GnomAD3 genomes

AF:

0.206

AC:

31298

AN:

151904

Hom.:

4518

Cov.:

show subpopulations

Gnomad AFR

AF:

0.381

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.295

Gnomad ASJ

AF:

0.175

Gnomad EAS

AF:

0.173

Gnomad SAS

AF:

0.142

Gnomad FIN

AF:

0.0682

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.112

Gnomad OTH

AF:

0.198

GnomAD2 exomes

AF:

0.176

AC:

44240

AN:

251438

AF XY:

0.163

show subpopulations

Gnomad AFR exome

AF:

0.394

Gnomad AMR exome

AF:

0.367

Gnomad ASJ exome

AF:

0.171

Gnomad EAS exome

AF:

0.183

Gnomad FIN exome

AF:

0.0752

Gnomad NFE exome

AF:

0.115

Gnomad OTH exome

AF:

0.141

GnomAD4 exome

AF:

0.133

AC:

193961

AN:

1461728

Hom.:

16137

Cov.:

AF XY:

0.131

AC XY:

95378

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.393

AC:

13139

AN:

33474

American (AMR)

AF:

0.357

AC:

15945

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.175

AC:

4582

AN:

26134

East Asian (EAS)

AF:

0.166

AC:

6593

AN:

39698

South Asian (SAS)

AF:

0.145

AC:

12548

AN:

86242

European-Finnish (FIN)

AF:

0.0740

AC:

3954

AN:

53398

Middle Eastern (MID)

AF:

0.158

AC:

909

AN:

5768

European-Non Finnish (NFE)

AF:

0.115

AC:

127319

AN:

1111914

Other (OTH)

AF:

0.149

AC:

8972

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

9476

18952

28427

37903

47379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5008

10016

15024

20032

25040

<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:

0.206

AC:

31363

AN:

152024

Hom.:

4532

Cov.:

AF XY:

0.204

AC XY:

15165

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.381

AC:

15776

AN:

41394

American (AMR)

AF:

0.296

AC:

4525

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.175

AC:

606

AN:

3470

East Asian (EAS)

AF:

0.173

AC:

896

AN:

5172

South Asian (SAS)

AF:

0.142

AC:

682

AN:

4810

European-Finnish (FIN)

AF:

0.0682

AC:

723

AN:

10598

Middle Eastern (MID)

AF:

0.184

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.112

AC:

7644

AN:

67986

Other (OTH)

AF:

0.200

AC:

422

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1104

2207

3311

4414

5518

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

302

604

906

1208

1510

<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:

0.148

Hom.:

9474

Bravo

AF:

0.233

TwinsUK

AF:

0.118

AC:

438

ALSPAC

AF:

0.115

AC:

443

ESP6500AA

AF:

0.377

AC:

1662

ESP6500EA

AF:

0.118

AC:

1019

ExAC

AF:

0.171

AC:

20761

Asia WGS

AF:

0.158

AC:

553

AN:

3478

EpiCase

AF:

0.121

EpiControl

AF:

0.124

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylcobalamin deficiency type cblE

Benign:4

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 19, 2021

Pars Genome 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 specified

Benign:2

Nov 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 29, 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. -

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

- -

Disorders of Intracellular Cobalamin Metabolism

Benign:1

Jan 12, 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

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

6.5

(source)

DANN

Benign

0.97

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.74

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.73

T;T

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.3

L;.

PhyloP100

1.2

PrimateAI

Benign

0.29

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.11

Sift

Benign

0.24

T;T

Sift4G

Benign

0.14

T;T

Vest4

0.024

MPC

0.050

ClinPred

0.0093

GERP RS

-2.2

Varity_R

0.099

gMVP

0.35

Mutation Taster

=97/3

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