rs1801394

Variant names:

• chr5-7870860-A-G
• rs1801394
• NM_002454.3:c.66A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16800 hom., cov: 34)
  • Exomes 𝑓: 0.53 (212709 hom.)
• Consequence: MTRR NM_002454.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:11 O:3
• Conservation: PhyloP100: 0.0980

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]

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a domain Flavodoxin-like (size 142) in uniprot entity MTRR_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) 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 [Likely_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 rank	MANE	Protein	UniProt
MTRR	NM_002454.3	c.66A>G	p.Ile22Met	missense_variant	Exon 2 of 15	ENST00000440940.7	NP_002445.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTRR	ENST00000440940.7	c.66A>G	p.Ile22Met	missense_variant	Exon 2 of 15	1	NM_002454.3	ENSP00000402510.2

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68524 AN: 152052 Hom.: 16801 Cov.: 34

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

GnomAD2 exomes AF: 0.466 AC: 117132 AN: 251460 AF XY: 0.482

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 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.: 50 AF XY: 0.534 AC XY: 387990 AN XY: 727196

Gnomad4 AFR exome AF: 0.275 AC: 9221 AN: 33476

Gnomad4 AMR exome AF: 0.264 AC: 11788 AN: 44724

Gnomad4 ASJ exome AF: 0.448 AC: 11718 AN: 26134

Gnomad4 EAS exome AF: 0.292 AC: 11591 AN: 39696

Gnomad4 SAS exome AF: 0.524 AC: 45222 AN: 86256

Gnomad4 FIN exome AF: 0.572 AC: 30549 AN: 53414

Gnomad4 NFE exome AF: 0.562 AC: 625139 AN: 1111936

Gnomad4 Remaining exome AF: 0.500 AC: 30197 AN: 60394

GnomAD4 genome AF: 0.450 AC: 68539 AN: 152170 Hom.: 16800 Cov.: 34 AF XY: 0.452 AC XY: 33597 AN XY: 74408

Gnomad4 AFR AF: 0.281 AC: 0.28114 AN: 0.28114

Gnomad4 AMR AF: 0.367 AC: 0.366745 AN: 0.366745

Gnomad4 ASJ AF: 0.456 AC: 0.456196 AN: 0.456196

Gnomad4 EAS AF: 0.283 AC: 0.28334 AN: 0.28334

Gnomad4 SAS AF: 0.529 AC: 0.529229 AN: 0.529229

Gnomad4 FIN AF: 0.578 AC: 0.578237 AN: 0.578237

Gnomad4 NFE AF: 0.557 AC: 0.557489 AN: 0.557489

Gnomad4 OTH AF: 0.426 AC: 0.426066 AN: 0.426066

Alfa AF: 0.508 Hom.: 91964

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/Likely benign

Submissions summary: Uncertain:1 Benign:11 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 26, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Methylcobalamin deficiency type cblE Benign:4

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 19, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gastrointestinal stromal tumor Uncertain:1

-

Department of Pharmacy and Biotechnology, University of Bologna

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Disorders of Intracellular Cobalamin Metabolism Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Down syndrome, susceptibility to Other:1

Jul 01, 2005

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neural tube defects, folate-sensitive, susceptibility to Other:1

Jul 01, 2005

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Methotrexate response Other:1

Apr 16, 2023

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

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

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	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.070
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.10	N
LIST_S2	Uncertain	0.92	D;D;D;D;D
MetaRNN	Benign	0.00045	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.3	M;.;.;.;.
PrimateAI	Uncertain	0.60	T
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	T
GERP RS		0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.37
gMVP		0.77
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1801394; hg19: chr5-7870973; COSMIC: COSV52943975; COSMIC: COSV52943975;