rs1801394

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_002454.3(MTRR):c.66A>G(p.Ile22Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 1,613,968 control chromosomes in the GnomAD database, including 229,509 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 16800 hom., cov: 34)

Exomes 𝑓: 0.53 ( 212709 hom. )

Consequence

MTRR
NM_002454.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:9O:3

Conservation

PhyloP100: 0.0980

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 -18 ACMG points.

PM1

In a domain Flavodoxin-like (size 142) in uniprot entity MTRR_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_002454.3

BP4

Computational evidence support a benign effect (MetaRNN=4.4935942E-4).

BP6

Variant 5-7870860-A-G is Benign according to our data. Variant chr5-7870860-A-G is described in ClinVar as [Benign]. Clinvar id is 7029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7870860-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.553 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.66A>G	p.Ile22Met	missense_variant	2/15	ENST00000440940.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTRR	ENST00000440940.7 linkuse as main transcript	c.66A>G	p.Ile22Met	missense_variant	2/15	1	NM_002454.3	P1	Q9UBK8-2

Frequencies

GnomAD3 genomes

AF:

0.451

AC:

68524

AN:

152052

Hom.:

16801

Cov.:

show subpopulations

Gnomad AFR

AF:

0.281

Gnomad AMI

AF:

0.676

Gnomad AMR

AF:

0.367

Gnomad ASJ

AF:

0.456

Gnomad EAS

AF:

0.283

Gnomad SAS

AF:

0.529

Gnomad FIN

AF:

0.578

Gnomad MID

AF:

0.385

Gnomad NFE

AF:

0.558

Gnomad OTH

AF:

0.430

GnomAD3 exomes

AF:

0.466

AC:

117132

AN:

251460

Hom.:

29891

AF XY:

0.482

AC XY:

65443

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.274

Gnomad AMR exome

AF:

0.250

Gnomad ASJ exome

AF:

0.455

Gnomad EAS exome

AF:

0.279

Gnomad SAS exome

AF:

0.525

Gnomad FIN exome

AF:

0.565

Gnomad NFE exome

AF:

0.554

Gnomad OTH exome

AF:

0.491

GnomAD4 exome

AF:

0.532

AC:

777894

AN:

1461798

Hom.:

212709

Cov.:

AF XY:

0.534

AC XY:

387990

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.275

Gnomad4 AMR exome

AF:

0.264

Gnomad4 ASJ exome

AF:

0.448

Gnomad4 EAS exome

AF:

0.292

Gnomad4 SAS exome

AF:

0.524

Gnomad4 FIN exome

AF:

0.572

Gnomad4 NFE exome

AF:

0.562

Gnomad4 OTH exome

AF:

0.500

GnomAD4 genome

AF:

0.450

AC:

68539

AN:

152170

Hom.:

16800

Cov.:

AF XY:

0.452

AC XY:

33597

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.281

Gnomad4 AMR

AF:

0.367

Gnomad4 ASJ

AF:

0.456

Gnomad4 EAS

AF:

0.283

Gnomad4 SAS

AF:

0.529

Gnomad4 FIN

AF:

0.578

Gnomad4 NFE

AF:

0.557

Gnomad4 OTH

AF:

0.426

Alfa

AF:

0.515

Hom.:

43514

Bravo

AF:

0.421

TwinsUK

AF:

0.553

AC:

2050

ALSPAC

AF:

0.565

AC:

2179

ESP6500AA

AF:

0.270

AC:

1188

ESP6500EA

AF:

0.546

AC:

4696

ExAC

AF:

0.473

AC:

57411

Asia WGS

AF:

0.387

AC:

1347

AN:

3478

EpiCase

AF:

0.529

EpiControl

AF:

0.524

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:9Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Methylcobalamin deficiency type cblE

Benign:4

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	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	- -

Gastrointestinal stromal tumor

Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

Department of Pharmacy and Biotechnology, University of Bologna

- -

Disorders of Intracellular Cobalamin Metabolism

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

Down syndrome, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 01, 2005

- -

Neural tube defects, folate-sensitive, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 01, 2005

- -

Methotrexate response

Other:1

drug response, no assertion criteria provided

research

Center of Excellence in Clinical Pharmacokinetics and Pharmacogenomics, Faculty of Medicine, Chulalongkorn University

Apr 16, 2023

There was a significant risk of acute kidney injury at 24 hours after methotrexate administration intravenously with MTRR rs1801394 allele A compared to variant allele G (OR (95%CI) = 2.084 (1.001-4.301), p = 0.047. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.090

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.070

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.10

LIST_S2

Uncertain

0.92

D;D;D;D;D

MetaRNN

Benign

0.00045

T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.3

M;.;.;.;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.2

N;N;D;D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.0020

D;D;D;T;D

Sift4G

Uncertain

0.0070

D;D;D;D;D

Vest4

0.26

MPC

0.32

ClinPred

0.049

GERP RS

0.33

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.37

gMVP

0.77

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