rs1532268

Positions:

chr5-7878066-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.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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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 criteria provided, multiple submitters, no conflicts U:1B:9

Conservation

PhyloP100: -2.35

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=0.0014089942).

BP6

Variant 5-7878066-C-T is Benign according to our data. Variant chr5-7878066-C-T is described in ClinVar as [Benign]. Clinvar id is 138304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7878066-C-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
MTRR	NM_002454.3 linkuse as main transcript	c.524C>T	p.Ser175Leu	missense_variant	5/15	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.524C>T	p.Ser175Leu	missense_variant	5/15	1	NM_002454.3	ENSP00000402510	P1	Q9UBK8-2

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

GnomAD3 exomes

AF:

0.311

AC:

78080

AN:

251244

Hom.:

13129

AF XY:

0.320

AC XY:

43445

AN XY:

135790

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 SAS exome

AF:

0.363

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

Gnomad4 AFR exome

AF:

0.269

Gnomad4 AMR exome

AF:

0.176

Gnomad4 ASJ exome

AF:

0.363

Gnomad4 EAS exome

AF:

0.123

Gnomad4 SAS exome

AF:

0.364

Gnomad4 FIN exome

AF:

0.323

Gnomad4 NFE exome

AF:

0.369

Gnomad4 OTH exome

AF:

0.348

GnomAD4 genome

AF:

0.316

AC:

47854

AN:

151578

Hom.:

7888

Cov.:

AF XY:

0.313

AC XY:

23148

AN XY:

74012

show subpopulations

Gnomad4 AFR

AF:

0.265

Gnomad4 AMR

AF:

0.240

Gnomad4 ASJ

AF:

0.369

Gnomad4 EAS

AF:

0.150

Gnomad4 SAS

AF:

0.377

Gnomad4 FIN

AF:

0.328

Gnomad4 NFE

AF:

0.366

Gnomad4 OTH

AF:

0.317

Alfa

AF:

0.354

Hom.:

20598

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

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylcobalamin deficiency type cblE

Benign:4

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Gastrointestinal stromal tumor

Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

Department of Pharmacy and Biotechnology, University of Bologna

- -

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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;.

MutationTaster

Benign

1.0

P;P;P

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

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

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