rs2287780

Positions:

chr5-7889191-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000440940.7(MTRR):c.1243C>T(p.Arg415Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 1,613,882 control chromosomes in the GnomAD database, including 2,191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.044 ( 274 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1917 hom. )

Consequence

MTRR
ENST00000440940.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.404

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=0.0017158389).

BP6

Variant 5-7889191-C-T is Benign according to our data. Variant chr5-7889191-C-T is described in ClinVar as [Benign]. Clinvar id is 138293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7889191-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.176 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.1243C>T	p.Arg415Cys	missense_variant	9/15	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.1243C>T	p.Arg415Cys	missense_variant	9/15	1	NM_002454.3	ENSP00000402510	P1	Q9UBK8-2

Frequencies

GnomAD3 genomes

AF:

0.0441

AC:

6702

AN:

152066

Hom.:

273

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0243

Gnomad AMI

AF:

0.0582

Gnomad AMR

AF:

0.0877

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.185

Gnomad SAS

AF:

0.0381

Gnomad FIN

AF:

0.0713

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0334

Gnomad OTH

AF:

0.0430

GnomAD3 exomes

AF:

0.0613

AC:

15425

AN:

251454

Hom.:

820

AF XY:

0.0557

AC XY:

7575

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0256

Gnomad AMR exome

AF:

0.140

Gnomad ASJ exome

AF:

0.0141

Gnomad EAS exome

AF:

0.184

Gnomad SAS exome

AF:

0.0344

Gnomad FIN exome

AF:

0.0700

Gnomad NFE exome

AF:

0.0332

Gnomad OTH exome

AF:

0.0472

GnomAD4 exome

AF:

0.0393

AC:

57382

AN:

1461698

Hom.:

1917

Cov.:

AF XY:

0.0386

AC XY:

28079

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.0232

Gnomad4 AMR exome

AF:

0.135

Gnomad4 ASJ exome

AF:

0.0139

Gnomad4 EAS exome

AF:

0.173

Gnomad4 SAS exome

AF:

0.0344

Gnomad4 FIN exome

AF:

0.0679

Gnomad4 NFE exome

AF:

0.0308

Gnomad4 OTH exome

AF:

0.0402

GnomAD4 genome

AF:

0.0441

AC:

6704

AN:

152184

Hom.:

274

Cov.:

AF XY:

0.0470

AC XY:

3494

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0244

Gnomad4 AMR

AF:

0.0876

Gnomad4 ASJ

AF:

0.0124

Gnomad4 EAS

AF:

0.185

Gnomad4 SAS

AF:

0.0379

Gnomad4 FIN

AF:

0.0713

Gnomad4 NFE

AF:

0.0334

Gnomad4 OTH

AF:

0.0416

Alfa

AF:

0.0364

Hom.:

377

Bravo

AF:

0.0448

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0337

AC:

130

ESP6500AA

AF:

0.0268

AC:

118

ESP6500EA

AF:

0.0281

AC:

242

ExAC

AF:

0.0566

AC:

6870

Asia WGS

AF:

0.117

AC:

406

AN:

3478

EpiCase

AF:

0.0266

EpiControl

AF:

0.0279

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

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

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 23, 2014

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

Jan 13, 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

0.084

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

0.011

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.85

D;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.6

D;D

REVEL

Benign

0.094

Sift

Uncertain

0.028

D;D

Sift4G

Uncertain

0.047

D;T

Vest4

0.15

MPC

0.088

ClinPred

0.033

GERP RS

4.2

Varity_R

0.22

gMVP

0.31

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