rs34172797

chr5-7892892-C-T

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.1536C>T(p.Ser512=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,614,144 control chromosomes in the GnomAD database, including 366 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (34 hom., cov: 33)
  • Exomes 𝑓: 0.020 (332 hom.)
• Consequence: MTRR NM_002454.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.367

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=-0.71).
• BP6: Variant 5-7892892-C-T is Benign according to our data. Variant chr5-7892892-C-T is described in ClinVar as [Benign]. Clinvar id is 138297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7892892-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.367 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0176 (2674/152314) while in subpopulation NFE AF= 0.0253 (1720/68024). AF 95% confidence interval is 0.0243. There are 34 homozygotes in gnomad4. There are 1261 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTRR	NM_002454.3	c.1536C>T	p.Ser512=	synonymous_variant	11/15	ENST00000440940.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTRR	ENST00000440940.7	c.1536C>T	p.Ser512=	synonymous_variant	11/15	1	NM_002454.3	P1

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2672 AN: 152196 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0253

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0157 AC: 3949 AN: 251208 Hom.: 30 AF XY: 0.0153 AC XY: 2074 AN XY: 135756

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.0161

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00258

Gnomad FIN exome AF: 0.0119

Gnomad NFE exome AF: 0.0230

Gnomad OTH exome AF: 0.0205

GnomAD4 exome AF: 0.0205 AC: 29913 AN: 1461830 Hom.: 332 Cov.: 31 AF XY: 0.0200 AC XY: 14515 AN XY: 727206

Gnomad4 AFR exome AF: 0.0110

Gnomad4 AMR exome AF: 0.0158

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00264

Gnomad4 FIN exome AF: 0.0125

Gnomad4 NFE exome AF: 0.0238

Gnomad4 OTH exome AF: 0.0188

GnomAD4 genome AF: 0.0176 AC: 2674 AN: 152314 Hom.: 34 Cov.: 33 AF XY: 0.0169 AC XY: 1261 AN XY: 74488

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.0143

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0121

Gnomad4 NFE AF: 0.0253

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0208 Hom.: 27

Bravo AF: 0.0179

Asia WGS AF: 0.00115 AC: 4 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	-0.71
Cadd	Benign	5.4
Dann	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs34172797; hg19: chr5-7893005;