chr5-7878311-T-A

Position:

chr5-7878311-T-A

Variant summary

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

The NM_002454.3(MTRR):c.769T>A(p.Ser257Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0333 in 1,613,958 control chromosomes in the GnomAD database, including 1,260 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 0.031 ( 136 hom., cov: 32)

Exomes 𝑓: 0.034 ( 1124 hom. )

Consequence

MTRR
NM_002454.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.75

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=0.0014932454).

BP6

Variant 5-7878311-T-A is Benign according to our data. Variant chr5-7878311-T-A is described in ClinVar as [Benign]. Clinvar id is 138306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7878311-T-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTRR	NM_002454.3 linkuse as main transcript	c.769T>A	p.Ser257Thr	missense_variant	5/15	ENST00000440940.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTRR	ENST00000440940.7 linkuse as main transcript	c.769T>A	p.Ser257Thr	missense_variant	5/15	1	NM_002454.3	P1	Q9UBK8-2

Frequencies

GnomAD3 genomes

AF:

0.0313

AC:

4760

AN:

152060

Hom.:

136

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00734

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.0441

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.109

Gnomad SAS

AF:

0.0210

Gnomad FIN

AF:

0.0702

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0327

Gnomad OTH

AF:

0.0283

GnomAD3 exomes

AF:

0.0432

AC:

10862

AN:

251340

Hom.:

346

AF XY:

0.0403

AC XY:

5480

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00691

Gnomad AMR exome

AF:

0.0772

Gnomad ASJ exome

AF:

0.0113

Gnomad EAS exome

AF:

0.110

Gnomad SAS exome

AF:

0.0163

Gnomad FIN exome

AF:

0.0694

Gnomad NFE exome

AF:

0.0327

Gnomad OTH exome

AF:

0.0354

GnomAD4 exome

AF:

0.0335

AC:

49017

AN:

1461780

Hom.:

1124

Cov.:

AF XY:

0.0329

AC XY:

23899

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.00517

Gnomad4 AMR exome

AF:

0.0751

Gnomad4 ASJ exome

AF:

0.0117

Gnomad4 EAS exome

AF:

0.108

Gnomad4 SAS exome

AF:

0.0172

Gnomad4 FIN exome

AF:

0.0674

Gnomad4 NFE exome

AF:

0.0305

Gnomad4 OTH exome

AF:

0.0307

GnomAD4 genome

AF:

0.0313

AC:

4758

AN:

152178

Hom.:

136

Cov.:

AF XY:

0.0331

AC XY:

2460

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00735

Gnomad4 AMR

AF:

0.0440

Gnomad4 ASJ

AF:

0.00980

Gnomad4 EAS

AF:

0.109

Gnomad4 SAS

AF:

0.0212

Gnomad4 FIN

AF:

0.0702

Gnomad4 NFE

AF:

0.0327

Gnomad4 OTH

AF:

0.0275

Alfa

AF:

0.0322

Hom.:

Bravo

AF:

0.0289

TwinsUK

AF:

0.0286

AC:

106

ALSPAC

AF:

0.0327

AC:

126

ESP6500AA

AF:

0.00931

AC:

ESP6500EA

AF:

0.0280

AC:

241

ExAC

AF:

0.0405

AC:

4920

Asia WGS

AF:

0.0640

AC:

224

AN:

3478

EpiCase

AF:

0.0261

EpiControl

AF:

0.0276

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylcobalamin deficiency type cblE

Benign:2

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

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.0040

DANN

Benign

0.24

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.43

T;T

MetaRNN

Benign

0.0015

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.46

N;N

REVEL

Benign

0.038

Sift

Benign

0.51

T;T

Sift4G

Benign

0.59

T;T

Vest4

0.028

MPC

0.044

ClinPred

0.0043

GERP RS

-12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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