rs2303080

chr5-7878311-T-A

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.769T>A(p.Ser257Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0333 in 1,613,958 control chromosomes in the GnomAD database, including 1,260 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 0.031 (136 hom., cov: 32)
  • Exomes 𝑓: 0.034 (1124 hom.)
• Consequence: MTRR NM_002454.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.75

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=0.0014932454).
• BP6: Variant 5-7878311-T-A is Benign according to our data. Variant chr5-7878311-T-A is described in ClinVar as [Benign]. Clinvar id is 138306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7878311-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTRR	NM_002454.3	c.769T>A	p.Ser257Thr	missense_variant	5/15	ENST00000440940.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTRR	ENST00000440940.7	c.769T>A	p.Ser257Thr	missense_variant	5/15	1	NM_002454.3	P1

Frequencies

GnomAD3 genomes AF: 0.0313 AC: 4760 AN: 152060 Hom.: 136 Cov.: 32

Gnomad AFR AF: 0.00734

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0441

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.0210

Gnomad FIN AF: 0.0702

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0327

Gnomad OTH AF: 0.0283

GnomAD3 exomes AF: 0.0432 AC: 10862 AN: 251340 Hom.: 346 AF XY: 0.0403 AC XY: 5480 AN XY: 135892

Gnomad AFR exome AF: 0.00691

Gnomad AMR exome AF: 0.0772

Gnomad ASJ exome AF: 0.0113

Gnomad EAS exome AF: 0.110

Gnomad SAS exome AF: 0.0163

Gnomad FIN exome AF: 0.0694

Gnomad NFE exome AF: 0.0327

Gnomad OTH exome AF: 0.0354

GnomAD4 exome AF: 0.0335 AC: 49017 AN: 1461780 Hom.: 1124 Cov.: 34 AF XY: 0.0329 AC XY: 23899 AN XY: 727182

Gnomad4 AFR exome AF: 0.00517

Gnomad4 AMR exome AF: 0.0751

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.108

Gnomad4 SAS exome AF: 0.0172

Gnomad4 FIN exome AF: 0.0674

Gnomad4 NFE exome AF: 0.0305

Gnomad4 OTH exome AF: 0.0307

GnomAD4 genome AF: 0.0313 AC: 4758 AN: 152178 Hom.: 136 Cov.: 32 AF XY: 0.0331 AC XY: 2460 AN XY: 74396

Gnomad4 AFR AF: 0.00735

Gnomad4 AMR AF: 0.0440

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.0212

Gnomad4 FIN AF: 0.0702

Gnomad4 NFE AF: 0.0327

Gnomad4 OTH AF: 0.0275

Alfa AF: 0.0322 Hom.: 85

Bravo AF: 0.0289

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0327 AC: 126

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.0280 AC: 241

ExAC AF: 0.0405 AC: 4920

Asia WGS AF: 0.0640 AC: 224 AN: 3478

EpiCase AF: 0.0261

EpiControl AF: 0.0276

ClinVar

Significance: Benign

Submissions summary: Benign:4

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	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.0040
Dann	Benign	0.24
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.43	T;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.46	N;N
REVEL	Benign	0.038
Sift	Benign	0.51	T;T
Sift4G	Benign	0.59	T;T
Vest4		0.028
MPC		0.044
ClinPred		0.0043	T
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.30

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: rs2303080; hg19: chr5-7878424;