5-7878066-C-T

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.524C>T(p.Ser175Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 1,613,402 control chromosomes in the GnomAD database, including 100,433 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S175P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.32 ( 7888 hom., cov: 30)

Exomes 𝑓: 0.35 ( 92545 hom. )

Consequence

MTRR
NM_002454.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:10

Conservation

PhyloP100: -2.35

Publications

133 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=0.0014089942).

BP6

Variant 5-7878066-C-T is Benign according to our data. Variant chr5-7878066-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRR	NM_002454.3 link	c.524C>T	p.Ser175Leu	missense_variant	Exon 5 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.524C>T	p.Ser175Leu	missense_variant	Exon 5 of 15	1	NM_002454.3	ENSP00000402510.2

Frequencies

GnomAD3 genomes

AF:

0.316

AC:

47805

AN:

151460

Hom.:

7871

Cov.:

show subpopulations

Gnomad AFR

AF:

0.265

Gnomad AMI

AF:

0.364

Gnomad AMR

AF:

0.241

Gnomad ASJ

AF:

0.369

Gnomad EAS

AF:

0.150

Gnomad SAS

AF:

0.376

Gnomad FIN

AF:

0.328

Gnomad MID

AF:

0.452

Gnomad NFE

AF:

0.366

Gnomad OTH

AF:

0.315

GnomAD2 exomes

AF:

0.311

AC:

78080

AN:

251244

AF XY:

0.320

show subpopulations

Gnomad AFR exome

AF:

0.263

Gnomad AMR exome

AF:

0.167

Gnomad ASJ exome

AF:

0.366

Gnomad EAS exome

AF:

0.158

Gnomad FIN exome

AF:

0.317

Gnomad NFE exome

AF:

0.364

Gnomad OTH exome

AF:

0.345

GnomAD4 exome

AF:

0.351

AC:

512993

AN:

1461824

Hom.:

92545

Cov.:

AF XY:

0.353

AC XY:

256369

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.269

AC:

9002

AN:

33480

American (AMR)

AF:

0.176

AC:

7851

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.363

AC:

9493

AN:

26132

East Asian (EAS)

AF:

0.123

AC:

4886

AN:

39700

South Asian (SAS)

AF:

0.364

AC:

31403

AN:

86258

European-Finnish (FIN)

AF:

0.323

AC:

17276

AN:

53410

Middle Eastern (MID)

AF:

0.398

AC:

2292

AN:

5766

European-Non Finnish (NFE)

AF:

0.369

AC:

409778

AN:

1111964

Other (OTH)

AF:

0.348

AC:

21012

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

20629

41258

61888

82517

103146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12754

25508

38262

51016

63770

<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:

0.316

AC:

47854

AN:

151578

Hom.:

7888

Cov.:

AF XY:

0.313

AC XY:

23148

AN XY:

74012

show subpopulations

African (AFR)

AF:

0.265

AC:

10970

AN:

41342

American (AMR)

AF:

0.240

AC:

3659

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.369

AC:

1278

AN:

3460

East Asian (EAS)

AF:

0.150

AC:

767

AN:

5114

South Asian (SAS)

AF:

0.377

AC:

1799

AN:

4776

European-Finnish (FIN)

AF:

0.328

AC:

3428

AN:

10448

Middle Eastern (MID)

AF:

0.455

AC:

133

AN:

292

European-Non Finnish (NFE)

AF:

0.366

AC:

24822

AN:

67876

Other (OTH)

AF:

0.317

AC:

666

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1584

3169

4753

6338

7922

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

492

984

1476

1968

2460

<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:

0.347

Hom.:

40447

Bravo

AF:

0.304

TwinsUK

AF:

0.373

AC:

1384

ALSPAC

AF:

0.365

AC:

1407

ESP6500AA

AF:

0.266

AC:

1172

ESP6500EA

AF:

0.360

AC:

3097

ExAC

AF:

0.315

AC:

38271

Asia WGS

AF:

0.293

AC:

1017

AN:

3478

EpiCase

AF:

0.366

EpiControl

AF:

0.369

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 26, 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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

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

Mar 06, 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

0.065

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.0060

(source)

DANN

Benign

0.69

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.23

T;T

MetaRNN

Benign

0.0014

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-1.2

N;.

PhyloP100

-2.4

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.66

N;N

REVEL

Benign

0.022

Sift

Benign

0.33

T;T

Sift4G

Benign

0.40

T;T

Vest4

0.026

MPC

0.043

ClinPred

0.019

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.017

gMVP

0.24

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