rs16879334

chr5-7891393-C-G

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.1349C>G(p.Pro450Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0376 in 1,605,388 control chromosomes in the GnomAD database, including 2,101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P450P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.041 (251 hom., cov: 30)
  • Exomes 𝑓: 0.037 (1850 hom.)
• Consequence: MTRR NM_002454.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.38

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=0.0036573112).
• BP6: Variant 5-7891393-C-G is Benign according to our data. Variant chr5-7891393-C-G is described in ClinVar as [Benign]. Clinvar id is 138294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7891393-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTRR	NM_002454.3	c.1349C>G	p.Pro450Arg	missense_variant	10/15	ENST00000440940.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTRR	ENST00000440940.7	c.1349C>G	p.Pro450Arg	missense_variant	10/15	1	NM_002454.3	P1

Frequencies

GnomAD3 genomes AF: 0.0407 AC: 6126 AN: 150694 Hom.: 250 Cov.: 30

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0862

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.0379

Gnomad FIN AF: 0.0704

Gnomad MID AF: 0.00962

Gnomad NFE AF: 0.0333

Gnomad OTH AF: 0.0394

GnomAD3 exomes AF: 0.0587 AC: 14689 AN: 250328 Hom.: 782 AF XY: 0.0535 AC XY: 7236 AN XY: 135356

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.135

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.180

Gnomad SAS exome AF: 0.0333

Gnomad FIN exome AF: 0.0691

Gnomad NFE exome AF: 0.0322

Gnomad OTH exome AF: 0.0451

GnomAD4 exome AF: 0.0372 AC: 54171 AN: 1454594 Hom.: 1850 Cov.: 30 AF XY: 0.0368 AC XY: 26646 AN XY: 724012

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.132

Gnomad4 ASJ exome AF: 0.0131

Gnomad4 EAS exome AF: 0.172

Gnomad4 SAS exome AF: 0.0334

Gnomad4 FIN exome AF: 0.0671

Gnomad4 NFE exome AF: 0.0290

Gnomad4 OTH exome AF: 0.0380

GnomAD4 genome AF: 0.0406 AC: 6128 AN: 150794 Hom.: 251 Cov.: 30 AF XY: 0.0439 AC XY: 3229 AN XY: 73578

Gnomad4 AFR AF: 0.0135

Gnomad4 AMR AF: 0.0861

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.184

Gnomad4 SAS AF: 0.0378

Gnomad4 FIN AF: 0.0704

Gnomad4 NFE AF: 0.0333

Gnomad4 OTH AF: 0.0381

Alfa AF: 0.0344 Hom.: 49

Bravo AF: 0.0412

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0330 AC: 127

ESP6500AA AF: 0.0143 AC: 63

ESP6500EA AF: 0.0280 AC: 241

ExAC AF: 0.0552 AC: 6697

Asia WGS AF: 0.115 AC: 398 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylcobalamin deficiency type cblE Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 23, 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	0.18
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Benign	0.0037	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Pathogenic	3.4	M;.
MutationTaster	Benign	9.0e-8	P;P
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0020	D;D
Vest4		0.17
MPC		0.31
ClinPred		0.082	T
GERP RS		5.2
Varity_R		0.58
gMVP		0.72

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: rs16879334; hg19: chr5-7891506; COSMIC: COSV99241341; COSMIC: COSV99241341;