rs1532268

Positions:

• chr5-7878066-C-T

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.524C>T​(p.Ser175Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 1,613,402 control chromosomes in the GnomAD database, including 100,433 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S175S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.32 (7888 hom., cov: 30)
  • Exomes 𝑓: 0.35 (92545 hom.)
• Consequence: MTRR NM_002454.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:8
• Conservation: PhyloP100: -2.35

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=0.0014089942).
• BP6: Variant 5-7878066-C-T is Benign according to our data. Variant chr5-7878066-C-T is described in ClinVar as [Benign]. Clinvar id is 138304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7878066-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTRR	NM_002454.3	c.524C>T	p.Ser175Leu	missense_variant	5/15	ENST00000440940.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTRR	ENST00000440940.7	c.524C>T	p.Ser175Leu	missense_variant	5/15	1	NM_002454.3	P1

Frequencies

GnomAD3 genomes AF: 0.316 AC: 47805 AN: 151460 Hom.: 7871 Cov.: 30

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.376

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.315

GnomAD3 exomes AF: 0.311 AC: 78080 AN: 251244 Hom.: 13129 AF XY: 0.320 AC XY: 43445 AN XY: 135790

Gnomad AFR exome AF: 0.263

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.366

Gnomad EAS exome AF: 0.158

Gnomad SAS exome AF: 0.363

Gnomad FIN exome AF: 0.317

Gnomad NFE exome AF: 0.364

Gnomad OTH exome AF: 0.345

GnomAD4 exome AF: 0.351 AC: 512993 AN: 1461824 Hom.: 92545 Cov.: 61 AF XY: 0.353 AC XY: 256369 AN XY: 727202

Gnomad4 AFR exome AF: 0.269

Gnomad4 AMR exome AF: 0.176

Gnomad4 ASJ exome AF: 0.363

Gnomad4 EAS exome AF: 0.123

Gnomad4 SAS exome AF: 0.364

Gnomad4 FIN exome AF: 0.323

Gnomad4 NFE exome AF: 0.369

Gnomad4 OTH exome AF: 0.348

GnomAD4 genome AF: 0.316 AC: 47854 AN: 151578 Hom.: 7888 Cov.: 30 AF XY: 0.313 AC XY: 23148 AN XY: 74012

Gnomad4 AFR AF: 0.265

Gnomad4 AMR AF: 0.240

Gnomad4 ASJ AF: 0.369

Gnomad4 EAS AF: 0.150

Gnomad4 SAS AF: 0.377

Gnomad4 FIN AF: 0.328

Gnomad4 NFE AF: 0.366

Gnomad4 OTH AF: 0.317

Alfa AF: 0.354 Hom.: 20598

Bravo AF: 0.304

TwinsUK AF: 0.373 AC: 1384

ALSPAC AF: 0.365 AC: 1407

ESP6500AA AF: 0.266 AC: 1172

ESP6500EA AF: 0.360 AC: 3097

ExAC AF: 0.315 AC: 38271

Asia WGS AF: 0.293 AC: 1017 AN: 3478

EpiCase AF: 0.366

EpiControl AF: 0.369

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylcobalamin deficiency type cblE Benign:4

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

Gastrointestinal stromal tumor Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

Department of Pharmacy and Biotechnology, University of Bologna

-

- -

Disorders of Intracellular Cobalamin Metabolism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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	0.065
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.0060
DANN	Benign	0.69
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.23	T;T
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.2	N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.66	N;N
REVEL	Benign	0.022
Sift	Benign	0.33	T;T
Sift4G	Benign	0.40	T;T
Vest4		0.026
MPC		0.043
ClinPred		0.019	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.017
gMVP		0.24

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: rs1532268; hg19: chr5-7878179; COSMIC: COSV52941765; COSMIC: COSV52941765;