rs162036

chr5-7885846-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002454.3(MTRR):c.1049A>G(p.Lys350Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,613,752 control chromosomes in the GnomAD database, including 20,669 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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 (16137 hom.)
• Consequence: MTRR NM_002454.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: 1.22

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026747882).
• BP6: Variant 5-7885846-A-G is Benign according to our data. Variant chr5-7885846-A-G is described in ClinVar as [Benign]. Clinvar id is 138291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7885846-A-G is described in Lovd as [Benign].
• 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	UniProt
MTRR	NM_002454.3	c.1049A>G	p.Lys350Arg	missense_variant	7/15	ENST00000440940.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTRR	ENST00000440940.7	c.1049A>G	p.Lys350Arg	missense_variant	7/15	1	NM_002454.3	P1

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31298 AN: 151904 Hom.: 4518 Cov.: 31

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0682

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.198

GnomAD3 exomes AF: 0.176 AC: 44240 AN: 251438 Hom.: 5490 AF XY: 0.163 AC XY: 22129 AN XY: 135900

Gnomad AFR exome AF: 0.394

Gnomad AMR exome AF: 0.367

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.183

Gnomad SAS exome AF: 0.146

Gnomad FIN exome AF: 0.0752

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.133 AC: 193961 AN: 1461728 Hom.: 16137 Cov.: 36 AF XY: 0.131 AC XY: 95378 AN XY: 727168

Gnomad4 AFR exome AF: 0.393

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: 0.149

GnomAD4 genome AF: 0.206 AC: 31363 AN: 152024 Hom.: 4532 Cov.: 31 AF XY: 0.204 AC XY: 15165 AN XY: 74302

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: 0.0682

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.200

Alfa AF: 0.137 Hom.: 3669

Bravo AF: 0.233

TwinsUK AF: 0.118 AC: 438

ALSPAC AF: 0.115 AC: 443

ESP6500AA AF: 0.377 AC: 1662

ESP6500EA AF: 0.118 AC: 1019

ExAC AF: 0.171 AC: 20761

Asia WGS AF: 0.158 AC: 553 AN: 3478

EpiCase AF: 0.121

EpiControl AF: 0.124

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylcobalamin deficiency type cblE Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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	- -

Gastrointestinal stromal tumor Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

Department of Pharmacy and Biotechnology, University of Bologna

-

- -

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 12, 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
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	6.5
Dann	Benign	0.97
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.74
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.73	T;T
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	0.0078	P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.11
Sift	Benign	0.24	T;T
Sift4G	Benign	0.14	T;T
Vest4		0.024
MPC		0.050
ClinPred		0.0093	T
GERP RS		-2.2
Varity_R		0.099
gMVP		0.35

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

Other links and lift over

dbSNP: rs162036; hg19: chr5-7885959; COSMIC: COSV52941474; COSMIC: COSV52941474;