rs1802059

Positions:

• chr5-7897206-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.55

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 -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	UniProt
MTRR	NM_002454.3	c.1911G>A	p.Ala637=	synonymous_variant	14/15	ENST00000440940.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTRR	ENST00000440940.7	c.1911G>A	p.Ala637=	synonymous_variant	14/15	1	NM_002454.3	P1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47414 AN: 151894 Hom.: 7774 Cov.: 32

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

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.: 54 AF XY: 0.352 AC XY: 255796 AN XY: 727186

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.: 32 AF XY: 0.310 AC XY: 23008 AN XY: 74324

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:8

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, 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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. -

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	-0.76
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

Other links and lift over

dbSNP: rs1802059; hg19: chr5-7897319; COSMIC: COSV52941525; COSMIC: COSV52941525;