chr5-7891393-C-G

Position:

chr5-7891393-C-G

Variant summary

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

The NM_002454.3(MTRR):c.1349C>G(p.Pro450Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0376 in 1,605,388 control chromosomes in the GnomAD database, including 2,101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.041 ( 251 hom., cov: 30)

Exomes 𝑓: 0.037 ( 1850 hom. )

Consequence

MTRR
NM_002454.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.38

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=0.0036573112).

BP6

Variant 5-7891393-C-G is Benign according to our data. Variant chr5-7891393-C-G is described in ClinVar as [Benign]. Clinvar id is 138294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7891393-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 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.1349C>G	p.Pro450Arg	missense_variant	10/15	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.1349C>G	p.Pro450Arg	missense_variant	10/15	1	NM_002454.3	ENSP00000402510	P1	Q9UBK8-2

Frequencies

GnomAD3 genomes

AF:

0.0407

AC:

6126

AN:

150694

Hom.:

250

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0133

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.0862

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.184

Gnomad SAS

AF:

0.0379

Gnomad FIN

AF:

0.0704

Gnomad MID

AF:

0.00962

Gnomad NFE

AF:

0.0333

Gnomad OTH

AF:

0.0394

GnomAD3 exomes

AF:

0.0587

AC:

14689

AN:

250328

Hom.:

782

AF XY:

0.0535

AC XY:

7236

AN XY:

135356

show subpopulations

Gnomad AFR exome

AF:

0.0131

Gnomad AMR exome

AF:

0.135

Gnomad ASJ exome

AF:

0.0130

Gnomad EAS exome

AF:

0.180

Gnomad SAS exome

AF:

0.0333

Gnomad FIN exome

AF:

0.0691

Gnomad NFE exome

AF:

0.0322

Gnomad OTH exome

AF:

0.0451

GnomAD4 exome

AF:

0.0372

AC:

54171

AN:

1454594

Hom.:

1850

Cov.:

AF XY:

0.0368

AC XY:

26646

AN XY:

724012

show subpopulations

Gnomad4 AFR exome

AF:

0.0103

Gnomad4 AMR exome

AF:

0.132

Gnomad4 ASJ exome

AF:

0.0131

Gnomad4 EAS exome

AF:

0.172

Gnomad4 SAS exome

AF:

0.0334

Gnomad4 FIN exome

AF:

0.0671

Gnomad4 NFE exome

AF:

0.0290

Gnomad4 OTH exome

AF:

0.0380

GnomAD4 genome

AF:

0.0406

AC:

6128

AN:

150794

Hom.:

251

Cov.:

AF XY:

0.0439

AC XY:

3229

AN XY:

73578

show subpopulations

Gnomad4 AFR

AF:

0.0135

Gnomad4 AMR

AF:

0.0861

Gnomad4 ASJ

AF:

0.0118

Gnomad4 EAS

AF:

0.184

Gnomad4 SAS

AF:

0.0378

Gnomad4 FIN

AF:

0.0704

Gnomad4 NFE

AF:

0.0333

Gnomad4 OTH

AF:

0.0381

Alfa

AF:

0.0344

Hom.:

Bravo

AF:

0.0412

TwinsUK

AF:

0.0286

AC:

106

ALSPAC

AF:

0.0330

AC:

127

ESP6500AA

AF:

0.0143

AC:

ESP6500EA

AF:

0.0280

AC:

241

ExAC

AF:

0.0552

AC:

6697

Asia WGS

AF:

0.115

AC:

398

AN:

3476

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

0.18

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D

MetaRNN

Benign

0.0037

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Pathogenic

3.4

M;.

MutationTaster

Benign

9.0e-8

P;P

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-6.1

D;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0020

D;D

Vest4

0.17

MPC

0.31

ClinPred

0.082

GERP RS

5.2

Varity_R

0.58

gMVP

0.72

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