5-7883243-T-C

Position:

chr5-7883243-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002454.3(MTRR):c.869T>C(p.Ile290Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00131 in 1,614,024 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00091 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 5 hom. )

Consequence

MTRR
NM_002454.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 6.84

Variant links:

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]

MTRR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.039203554).

BP6

Variant 5-7883243-T-C is Benign according to our data. Variant chr5-7883243-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 354357.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000907 (138/152226) while in subpopulation NFE AF= 0.00171 (116/68026). AF 95% confidence interval is 0.00145. There are 0 homozygotes in gnomad4. There are 60 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTRR	NM_002454.3 linkuse as main transcript	c.869T>C	p.Ile290Thr	missense_variant	6/15	ENST00000440940.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTRR	ENST00000440940.7 linkuse as main transcript	c.869T>C	p.Ile290Thr	missense_variant	6/15	1	NM_002454.3	P1	Q9UBK8-2

Frequencies

GnomAD3 genomes

AF:

0.000907

AC:

138

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00171

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000955

AC:

240

AN:

251436

Hom.:

AF XY:

0.000964

AC XY:

131

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.00193

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.00135

AC:

1971

AN:

1461798

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

937

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000374

Gnomad4 NFE exome

AF:

0.00169

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.000907

AC:

138

AN:

152226

Hom.:

Cov.:

AF XY:

0.000807

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.000338

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00171

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.00139

Hom.:

Bravo

AF:

0.000869

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00105

AC:

127

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00180

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Methylcobalamin deficiency type cblE

Uncertain:1Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 15, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge, in association with a MTRR-related disorder; This variant is associated with the following publications: (PMID: 31063268) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 05, 2022	The MTRR c.869T>C; p.Ile290Thr variant (rs144899305), to our knowledge, is not reported in an individual with homocystinuria-megaloblastic anemia, but is reported in the literature in an individual with cleft lip (Marini 2019). This variant is reported in ClinVar (Variation ID: 354357) and is found in the non-Finnish European population with an allele frequency of 0.18% (233/129,162 alleles) in the Genome Aggregation Database. The isoleucine at codon 290 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.148). Due to limited information, the clinical significance of the p.Ile290Thr variant is uncertain at this time. References: Marini NJ et al. Accumulation of rare coding variants in genes implicated in risk of human cleft lip with or without cleft palate. Am J Med Genet A. 2019 Jul;179(7):1260-1269. PMID: 31063268. -

Disorders of Intracellular Cobalamin Metabolism

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

1.0

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.039

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.1

L;.

MutationTaster

Benign

0.73

D;D;D

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.7

D;D

REVEL

Benign

0.15

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.019

D;D

Vest4

0.29

MVP

0.80

MPC

0.20

ClinPred

0.061

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.43

gMVP

0.47

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over