rs161870

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002454.3(MTRR):c.537T>C(p.Leu179Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,613,688 control chromosomes in the GnomAD database, including 20,659 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 4532 hom., cov: 31)

Exomes 𝑓: 0.13 ( 16127 hom. )

Consequence

MTRR
NM_002454.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -3.79

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:

MTRR (HGNC:):

MTRR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 5-7878079-T-C is Benign according to our data. Variant chr5-7878079-T-C is described in ClinVar as [Benign]. Clinvar id is 138305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7878079-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.79 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.376 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.537T>C	p.Leu179Leu	synonymous_variant	5/15	ENST00000440940.7	NP_002445.2	Q9UBK8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTRR	ENST00000440940.7 linkuse as main transcript	c.537T>C	p.Leu179Leu	synonymous_variant	5/15	1	NM_002454.3	ENSP00000402510.2		Q9UBK8-2

Frequencies

GnomAD3 genomes

AF:

0.206

AC:

31265

AN:

151714

Hom.:

4518

Cov.:

show subpopulations

Gnomad AFR

AF:

0.382

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.294

Gnomad ASJ

AF:

0.175

Gnomad EAS

AF:

0.173

Gnomad SAS

AF:

0.142

Gnomad FIN

AF:

0.0683

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.112

Gnomad OTH

AF:

0.199

GnomAD3 exomes

AF:

0.176

AC:

44201

AN:

251326

Hom.:

5482

AF XY:

0.163

AC XY:

22109

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.394

Gnomad AMR exome

AF:

0.368

Gnomad ASJ exome

AF:

0.171

Gnomad EAS exome

AF:

0.184

Gnomad SAS exome

AF:

0.146

Gnomad FIN exome

AF:

0.0751

Gnomad NFE exome

AF:

0.115

Gnomad OTH exome

AF:

0.141

GnomAD4 exome

AF:

0.133

AC:

193954

AN:

1461856

Hom.:

16127

Cov.:

AF XY:

0.131

AC XY:

95368

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.392

Gnomad4 AMR exome

AF:

0.357

Gnomad4 ASJ exome

AF:

0.175

Gnomad4 EAS exome

AF:

0.166

Gnomad4 SAS exome

AF:

0.145

Gnomad4 FIN exome

AF:

0.0740

Gnomad4 NFE exome

AF:

0.115

Gnomad4 OTH exome

AF:

0.148

GnomAD4 genome

AF:

0.206

AC:

31329

AN:

151832

Hom.:

4532

Cov.:

AF XY:

0.204

AC XY:

15159

AN XY:

74198

show subpopulations

Gnomad4 AFR

AF:

0.381

Gnomad4 AMR

AF:

0.296

Gnomad4 ASJ

AF:

0.175

Gnomad4 EAS

AF:

0.173

Gnomad4 SAS

AF:

0.142

Gnomad4 FIN

AF:

0.0683

Gnomad4 NFE

AF:

0.112

Gnomad4 OTH

AF:

0.200

Alfa

AF:

0.152

Hom.:

1199

Bravo

AF:

0.233

Asia WGS

AF:

0.158

AC:

551

AN:

3478

EpiCase

AF:

0.121

EpiControl

AF:

0.125

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylcobalamin deficiency type cblE

Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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	- -

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

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

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.14

DANN

Benign

0.45

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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