rs139206262

Positions:

chr5-7895829-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_002454.3(MTRR):c.1653G>A(p.Pro551Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00981 in 1,614,060 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0069 ( 4 hom., cov: 32)

Exomes 𝑓: 0.010 ( 91 hom. )

Consequence

MTRR
NM_002454.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.143

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 5-7895829-G-A is Benign according to our data. Variant chr5-7895829-G-A is described in ClinVar as [Benign]. Clinvar id is 203840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7895829-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.143 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00693 (1055/152266) while in subpopulation NFE AF= 0.0115 (784/68000). AF 95% confidence interval is 0.0109. There are 4 homozygotes in gnomad4. There are 527 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTRR	NM_002454.3 linkuse as main transcript	c.1653G>A	p.Pro551Pro	synonymous_variant	12/15	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.1653G>A	p.Pro551Pro	synonymous_variant	12/15	1	NM_002454.3	ENSP00000402510.2		Q9UBK8-2

Frequencies

GnomAD3 genomes

AF:

0.00695

AC:

1057

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00452

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00704

Gnomad FIN

AF:

0.00706

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0115

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00803

AC:

2019

AN:

251430

Hom.:

AF XY:

0.00824

AC XY:

1120

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.00275

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00657

Gnomad FIN exome

AF:

0.00970

Gnomad NFE exome

AF:

0.0125

Gnomad OTH exome

AF:

0.00619

GnomAD4 exome

AF:

0.0101

AC:

14776

AN:

1461794

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

7336

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00119

Gnomad4 AMR exome

AF:

0.00253

Gnomad4 ASJ exome

AF:

0.00210

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00716

Gnomad4 FIN exome

AF:

0.00962

Gnomad4 NFE exome

AF:

0.0116

Gnomad4 OTH exome

AF:

0.00803

GnomAD4 genome

AF:

0.00693

AC:

1055

AN:

152266

Hom.:

Cov.:

AF XY:

0.00708

AC XY:

527

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00171

Gnomad4 AMR

AF:

0.00445

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00684

Gnomad4 FIN

AF:

0.00706

Gnomad4 NFE

AF:

0.0115

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00845

Hom.:

Bravo

AF:

0.00609

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.00981

EpiControl

AF:

0.00907

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	MTRR: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Aug 11, 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

BayesDel_noAF

Benign

-0.45

CADD

Benign

7.9

DANN

Benign

0.54

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