rs10380

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.1783C>T(p.His595Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,613,374 control chromosomes in the GnomAD database, including 15,754 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. H595R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.18 ( 3416 hom., cov: 32)

Exomes 𝑓: 0.11 ( 12338 hom. )

Consequence

MTRR
NM_002454.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.559

Publications

87 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=0.012291789).

BP6

Variant 5-7897078-C-T is Benign according to our data. Variant chr5-7897078-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRR	NM_002454.3 link	c.1783C>T	p.His595Tyr	missense_variant	Exon 14 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.1783C>T	p.His595Tyr	missense_variant	Exon 14 of 15	1	NM_002454.3	ENSP00000402510.2		Q9UBK8-2

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27185

AN:

152012

Hom.:

3398

Cov.:

show subpopulations

Gnomad AFR

AF:

0.328

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.272

Gnomad ASJ

AF:

0.155

Gnomad EAS

AF:

0.147

Gnomad SAS

AF:

0.136

Gnomad FIN

AF:

0.0646

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.0940

Gnomad OTH

AF:

0.169

GnomAD2 exomes

AF:

0.157

AC:

39347

AN:

250918

AF XY:

0.145

show subpopulations

Gnomad AFR exome

AF:

0.335

Gnomad AMR exome

AF:

0.353

Gnomad ASJ exome

AF:

0.151

Gnomad EAS exome

AF:

0.158

Gnomad FIN exome

AF:

0.0699

Gnomad NFE exome

AF:

0.0952

Gnomad OTH exome

AF:

0.124

GnomAD4 exome

AF:

0.113

AC:

165838

AN:

1461244

Hom.:

12338

Cov.:

AF XY:

0.112

AC XY:

81709

AN XY:

726952

show subpopulations

African (AFR)

AF:

0.334

AC:

11177

AN:

33454

American (AMR)

AF:

0.341

AC:

15257

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.155

AC:

4061

AN:

26128

East Asian (EAS)

AF:

0.140

AC:

5567

AN:

39690

South Asian (SAS)

AF:

0.137

AC:

11829

AN:

86236

European-Finnish (FIN)

AF:

0.0682

AC:

3641

AN:

53408

Middle Eastern (MID)

AF:

0.142

AC:

818

AN:

5768

European-Non Finnish (NFE)

AF:

0.0951

AC:

105727

AN:

1111504

Other (OTH)

AF:

0.129

AC:

7761

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

7595

15190

22786

30381

37976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4254

8508

12762

17016

21270

<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:

0.179

AC:

27246

AN:

152130

Hom.:

3416

Cov.:

AF XY:

0.178

AC XY:

13263

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.328

AC:

13603

AN:

41466

American (AMR)

AF:

0.273

AC:

4170

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.155

AC:

537

AN:

3470

East Asian (EAS)

AF:

0.147

AC:

762

AN:

5174

South Asian (SAS)

AF:

0.136

AC:

653

AN:

4818

European-Finnish (FIN)

AF:

0.0646

AC:

685

AN:

10606

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0940

AC:

6391

AN:

68004

Other (OTH)

AF:

0.172

AC:

363

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1053

2106

3160

4213

5266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

268

536

804

1072

1340

<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:

0.126

Hom.:

7703

Bravo

AF:

0.203

TwinsUK

AF:

0.0952

AC:

353

ALSPAC

AF:

0.0911

AC:

351

ESP6500AA

AF:

0.320

AC:

1410

ESP6500EA

AF:

0.0978

AC:

841

ExAC

AF:

0.151

AC:

18324

Asia WGS

AF:

0.145

AC:

505

AN:

3478

EpiCase

AF:

0.100

EpiControl

AF:

0.102

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:3

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. -

not provided

Benign:2

Nov 14, 2024

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

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.47

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.17

T;T

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;.

PhyloP100

0.56

PrimateAI

Benign

0.27

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.18

Sift

Benign

0.12

T;T

Sift4G

Benign

0.18

T;T

Vest4

0.065

MPC

0.052

ClinPred

0.0019

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.065

gMVP

0.39

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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