rs10380

Positions:

chr5-7897078-C-T

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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 criteria provided, multiple submitters, no conflicts U:1B:7

Conservation

PhyloP100: 0.559

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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]. Clinvar id is 138300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7897078-C-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
MTRR	NM_002454.3 linkuse as main transcript	c.1783C>T	p.His595Tyr	missense_variant	14/15	ENST00000440940.7	NP_002445.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTRR	ENST00000440940.7 linkuse as main transcript	c.1783C>T	p.His595Tyr	missense_variant	14/15	1	NM_002454.3	ENSP00000402510	P1	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

GnomAD3 exomes

AF:

0.157

AC:

39347

AN:

250918

Hom.:

4573

AF XY:

0.145

AC XY:

19635

AN XY:

135632

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 SAS exome

AF:

0.139

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

Gnomad4 AFR exome

AF:

0.334

Gnomad4 AMR exome

AF:

0.341

Gnomad4 ASJ exome

AF:

0.155

Gnomad4 EAS exome

AF:

0.140

Gnomad4 SAS exome

AF:

0.137

Gnomad4 FIN exome

AF:

0.0682

Gnomad4 NFE exome

AF:

0.0951

Gnomad4 OTH exome

AF:

0.129

GnomAD4 genome

AF:

0.179

AC:

27246

AN:

152130

Hom.:

3416

Cov.:

AF XY:

0.178

AC XY:

13263

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.328

Gnomad4 AMR

AF:

0.273

Gnomad4 ASJ

AF:

0.155

Gnomad4 EAS

AF:

0.147

Gnomad4 SAS

AF:

0.136

Gnomad4 FIN

AF:

0.0646

Gnomad4 NFE

AF:

0.0940

Gnomad4 OTH

AF:

0.172

Alfa

AF:

0.117

Hom.:

3322

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

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylcobalamin deficiency type cblE

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 19, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Gastrointestinal stromal tumor

Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

Department of Pharmacy and Biotechnology, University of Bologna

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 29, 2013

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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

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;.

MutationTaster

Benign

1.0

P;P

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over