rs2303080

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.769T>A(p.Ser257Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0333 in 1,613,958 control chromosomes in the GnomAD database, including 1,260 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 Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 136 hom., cov: 32)

Exomes 𝑓: 0.034 ( 1124 hom. )

Consequence

MTRR
NM_002454.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.75

Publications

35 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=0.0014932454).

BP6

Variant 5-7878311-T-A is Benign according to our data. Variant chr5-7878311-T-A is described in ClinVar as Benign. ClinVar VariationId is 138306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRR	NM_002454.3 link	c.769T>A	p.Ser257Thr	missense_variant	Exon 5 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.769T>A	p.Ser257Thr	missense_variant	Exon 5 of 15	1	NM_002454.3	ENSP00000402510.2		Q9UBK8-2

Frequencies

GnomAD3 genomes

AF:

0.0313

AC:

4760

AN:

152060

Hom.:

136

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00734

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.0441

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.109

Gnomad SAS

AF:

0.0210

Gnomad FIN

AF:

0.0702

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0327

Gnomad OTH

AF:

0.0283

GnomAD2 exomes

AF:

0.0432

AC:

10862

AN:

251340

AF XY:

0.0403

show subpopulations

Gnomad AFR exome

AF:

0.00691

Gnomad AMR exome

AF:

0.0772

Gnomad ASJ exome

AF:

0.0113

Gnomad EAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.0694

Gnomad NFE exome

AF:

0.0327

Gnomad OTH exome

AF:

0.0354

GnomAD4 exome

AF:

0.0335

AC:

49017

AN:

1461780

Hom.:

1124

Cov.:

AF XY:

0.0329

AC XY:

23899

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.00517

AC:

173

AN:

33478

American (AMR)

AF:

0.0751

AC:

3361

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0117

AC:

305

AN:

26136

East Asian (EAS)

AF:

0.108

AC:

4295

AN:

39700

South Asian (SAS)

AF:

0.0172

AC:

1480

AN:

86256

European-Finnish (FIN)

AF:

0.0674

AC:

3599

AN:

53420

Middle Eastern (MID)

AF:

0.00485

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0305

AC:

33921

AN:

1111904

Other (OTH)

AF:

0.0307

AC:

1855

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

2687

5374

8062

10749

13436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1302

2604

3906

5208

6510

<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:

0.0313

AC:

4758

AN:

152178

Hom.:

136

Cov.:

AF XY:

0.0331

AC XY:

2460

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00735

AC:

305

AN:

41518

American (AMR)

AF:

0.0440

AC:

673

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00980

AC:

AN:

3470

East Asian (EAS)

AF:

0.109

AC:

565

AN:

5172

South Asian (SAS)

AF:

0.0212

AC:

102

AN:

4812

European-Finnish (FIN)

AF:

0.0702

AC:

743

AN:

10584

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0327

AC:

2222

AN:

68010

Other (OTH)

AF:

0.0275

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

235

469

704

938

1173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0322

Hom.:

Bravo

AF:

0.0289

TwinsUK

AF:

0.0286

AC:

106

ALSPAC

AF:

0.0327

AC:

126

ESP6500AA

AF:

0.00931

AC:

ESP6500EA

AF:

0.0280

AC:

241

ExAC

AF:

0.0405

AC:

4920

Asia WGS

AF:

0.0640

AC:

224

AN:

3478

EpiCase

AF:

0.0261

EpiControl

AF:

0.0276

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

Mar 12, 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

0.072

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.0040

(source)

DANN

Benign

0.24

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.43

T;T

MetaRNN

Benign

0.0015

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;.

PhyloP100

-2.7

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.46

N;N

REVEL

Benign

0.038

Sift

Benign

0.51

T;T

Sift4G

Benign

0.59

T;T

Vest4

0.028

MPC

0.044

ClinPred

0.0043

GERP RS

-12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.30

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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