rs35890938

Positions:

• chr5-7892820-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002454.3(MTRR):​c.1464A>G​(p.Val488=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,614,200 control chromosomes in the GnomAD database, including 364 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (33 hom., cov: 33)
  • Exomes 𝑓: 0.020 (331 hom.)
• Consequence: MTRR NM_002454.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.248

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=-0.66).
• BP6: Variant 5-7892820-A-G is Benign according to our data. Variant chr5-7892820-A-G is described in ClinVar as [Benign]. Clinvar id is 138296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7892820-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.248 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0165 (2510/152316) while in subpopulation NFE AF= 0.0253 (1718/68018). AF 95% confidence interval is 0.0243. There are 33 homozygotes in gnomad4. There are 1195 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTRR	NM_002454.3	c.1464A>G	p.Val488=	synonymous_variant	11/15	ENST00000440940.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTRR	ENST00000440940.7	c.1464A>G	p.Val488=	synonymous_variant	11/15	1	NM_002454.3	P1

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2509 AN: 152198 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.00733

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0253

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.0154 AC: 3867 AN: 251462 Hom.: 29 AF XY: 0.0150 AC XY: 2039 AN XY: 135902

Gnomad AFR exome AF: 0.00769

Gnomad AMR exome AF: 0.0161

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00255

Gnomad FIN exome AF: 0.0119

Gnomad NFE exome AF: 0.0229

Gnomad OTH exome AF: 0.0205

GnomAD4 exome AF: 0.0203 AC: 29668 AN: 1461884 Hom.: 331 Cov.: 31 AF XY: 0.0198 AC XY: 14416 AN XY: 727242

Gnomad4 AFR exome AF: 0.00672

Gnomad4 AMR exome AF: 0.0157

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00262

Gnomad4 FIN exome AF: 0.0125

Gnomad4 NFE exome AF: 0.0237

Gnomad4 OTH exome AF: 0.0186

GnomAD4 genome AF: 0.0165 AC: 2510 AN: 152316 Hom.: 33 Cov.: 33 AF XY: 0.0160 AC XY: 1195 AN XY: 74474

Gnomad4 AFR AF: 0.00733

Gnomad4 AMR AF: 0.0140

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.0122

Gnomad4 NFE AF: 0.0253

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0204 Hom.: 19

Bravo AF: 0.0167

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0220

EpiControl AF: 0.0182

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylcobalamin deficiency type cblE Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 16, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.8
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs35890938; hg19: chr5-7892933;