rs1802059

Positions:

chr5-7897206-G-A

Variant summary

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

The NM_002454.3(MTRR):c.1911G>A(p.Ala637=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 1,613,790 control chromosomes in the GnomAD database, including 99,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7789 hom., cov: 32)

Exomes 𝑓: 0.35 ( 92166 hom. )

Consequence

MTRR
NM_002454.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.55

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 5-7897206-G-A is Benign according to our data. Variant chr5-7897206-G-A is described in ClinVar as [Benign]. Clinvar id is 138302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7897206-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.55 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.366 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.1911G>A	p.Ala637=	synonymous_variant	14/15	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.1911G>A	p.Ala637=	synonymous_variant	14/15	1	NM_002454.3	ENSP00000402510	P1	Q9UBK8-2

Frequencies

GnomAD3 genomes

AF:

0.312

AC:

47414

AN:

151894

Hom.:

7774

Cov.:

show subpopulations

Gnomad AFR

AF:

0.253

Gnomad AMI

AF:

0.363

Gnomad AMR

AF:

0.239

Gnomad ASJ

AF:

0.372

Gnomad EAS

AF:

0.151

Gnomad SAS

AF:

0.379

Gnomad FIN

AF:

0.328

Gnomad MID

AF:

0.440

Gnomad NFE

AF:

0.365

Gnomad OTH

AF:

0.315

GnomAD3 exomes

AF:

0.310

AC:

77864

AN:

251334

Hom.:

13076

AF XY:

0.319

AC XY:

43344

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.251

Gnomad AMR exome

AF:

0.166

Gnomad ASJ exome

AF:

0.368

Gnomad EAS exome

AF:

0.159

Gnomad SAS exome

AF:

0.363

Gnomad FIN exome

AF:

0.317

Gnomad NFE exome

AF:

0.364

Gnomad OTH exome

AF:

0.344

GnomAD4 exome

AF:

0.350

AC:

511732

AN:

1461778

Hom.:

92166

Cov.:

AF XY:

0.352

AC XY:

255796

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.258

Gnomad4 AMR exome

AF:

0.175

Gnomad4 ASJ exome

AF:

0.365

Gnomad4 EAS exome

AF:

0.124

Gnomad4 SAS exome

AF:

0.365

Gnomad4 FIN exome

AF:

0.323

Gnomad4 NFE exome

AF:

0.368

Gnomad4 OTH exome

AF:

0.347

GnomAD4 genome

AF:

0.312

AC:

47460

AN:

152012

Hom.:

7789

Cov.:

AF XY:

0.310

AC XY:

23008

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.254

Gnomad4 AMR

AF:

0.238

Gnomad4 ASJ

AF:

0.372

Gnomad4 EAS

AF:

0.151

Gnomad4 SAS

AF:

0.380

Gnomad4 FIN

AF:

0.328

Gnomad4 NFE

AF:

0.365

Gnomad4 OTH

AF:

0.316

Alfa

AF:

0.351

Hom.:

12133

Bravo

AF:

0.300

Asia WGS

AF:

0.298

AC:

1035

AN:

3478

EpiCase

AF:

0.365

EpiControl

AF:

0.369

ClinVar

Significance: Benign

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

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Clinical Genetics, Academic Medical Center	-	- -

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

-0.76

CADD

Benign

0.70

DANN

Benign

0.78

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