rs2287780

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.1243C>T(p.Arg415Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 1,613,882 control chromosomes in the GnomAD database, including 2,191 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.044 ( 274 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1917 hom. )

Consequence

MTRR
NM_002454.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.404

Publications

43 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=0.0017158389).

BP6

Variant 5-7889191-C-T is Benign according to our data. Variant chr5-7889191-C-T is described in ClinVar as Benign. ClinVar VariationId is 138293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRR	NM_002454.3 link	c.1243C>T	p.Arg415Cys	missense_variant	Exon 9 of 15	ENST00000440940.7	NP_002445.2	Q9UBK8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTRR	ENST00000440940.7 link	c.1243C>T	p.Arg415Cys	missense_variant	Exon 9 of 15	1	NM_002454.3	ENSP00000402510.2		Q9UBK8-2

Frequencies

GnomAD3 genomes

AF:

0.0441

AC:

6702

AN:

152066

Hom.:

273

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0243

Gnomad AMI

AF:

0.0582

Gnomad AMR

AF:

0.0877

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.185

Gnomad SAS

AF:

0.0381

Gnomad FIN

AF:

0.0713

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0334

Gnomad OTH

AF:

0.0430

GnomAD2 exomes

AF:

0.0613

AC:

15425

AN:

251454

AF XY:

0.0557

show subpopulations

Gnomad AFR exome

AF:

0.0256

Gnomad AMR exome

AF:

0.140

Gnomad ASJ exome

AF:

0.0141

Gnomad EAS exome

AF:

0.184

Gnomad FIN exome

AF:

0.0700

Gnomad NFE exome

AF:

0.0332

Gnomad OTH exome

AF:

0.0472

GnomAD4 exome

AF:

0.0393

AC:

57382

AN:

1461698

Hom.:

1917

Cov.:

AF XY:

0.0386

AC XY:

28079

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.0232

AC:

776

AN:

33476

American (AMR)

AF:

0.135

AC:

6042

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0139

AC:

362

AN:

26136

East Asian (EAS)

AF:

0.173

AC:

6881

AN:

39700

South Asian (SAS)

AF:

0.0344

AC:

2969

AN:

86248

European-Finnish (FIN)

AF:

0.0679

AC:

3629

AN:

53416

Middle Eastern (MID)

AF:

0.00677

AC:

AN:

5612

European-Non Finnish (NFE)

AF:

0.0308

AC:

34260

AN:

1112004

Other (OTH)

AF:

0.0402

AC:

2425

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

3188

6375

9563

12750

15938

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1400

2800

4200

5600

7000

<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:

0.0441

AC:

6704

AN:

152184

Hom.:

274

Cov.:

AF XY:

0.0470

AC XY:

3494

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.0244

AC:

1014

AN:

41532

American (AMR)

AF:

0.0876

AC:

1338

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

AN:

3472

East Asian (EAS)

AF:

0.185

AC:

955

AN:

5154

South Asian (SAS)

AF:

0.0379

AC:

183

AN:

4824

European-Finnish (FIN)

AF:

0.0713

AC:

756

AN:

10596

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0334

AC:

2271

AN:

68008

Other (OTH)

AF:

0.0416

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

313

626

938

1251

1564

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0382

Hom.:

747

Bravo

AF:

0.0448

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0337

AC:

130

ESP6500AA

AF:

0.0268

AC:

118

ESP6500EA

AF:

0.0281

AC:

242

ExAC

AF:

0.0566

AC:

6870

Asia WGS

AF:

0.117

AC:

406

AN:

3478

EpiCase

AF:

0.0266

EpiControl

AF:

0.0279

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylcobalamin deficiency type cblE

Benign:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

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:1

Jan 23, 2014

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

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

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

0.011

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.85

D;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

0.40

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.6

D;D

REVEL

Benign

0.094

Sift

Uncertain

0.028

D;D

Sift4G

Uncertain

0.047

D;T

Vest4

0.15

MPC

0.088

ClinPred

0.033

GERP RS

4.2

Varity_R

0.22

gMVP

0.31

Mutation Taster

=93/7

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