5-139329372-C-T

Position:

chr5-139329372-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_ModerateBP6_Very_StrongBS2

The NM_018834.6(MATR3):c.2521C>T(p.Arg841Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000332 in 1,611,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

MATR3
NM_018834.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.72

Variant links:

Genes affected

MATR3 (HGNC:6912): (matrin 3) This gene encodes a nuclear matrix protein, which is proposed to stabilize certain messenger RNA species. Mutations of this gene are associated with distal myopathy 2, which often includes vocal cord and pharyngeal weakness. Alternatively spliced transcript variants, including read-through transcripts composed of the upstream small nucleolar RNA host gene 4 (non-protein coding) and matrin 3 gene sequence, have been identified. Pseudogenes of this gene are located on chromosomes 1 and X. [provided by RefSeq, Aug 2013]

MATR3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MATR3. . Gene score misZ 2.7297 (greater than the threshold 3.09). Trascript score misZ 3.9451 (greater than threshold 3.09). GenCC has associacion of gene with amyotrophic lateral sclerosis, distal myopathy with vocal cord weakness, amyotrophic lateral sclerosis type 21.

BP4

Computational evidence support a benign effect (MetaRNN=0.12200549).

BP6

Variant 5-139329372-C-T is Benign according to our data. Variant chr5-139329372-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 351143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MATR3	NM_018834.6 linkuse as main transcript	c.2521C>T	p.Arg841Cys	missense_variant	15/15	ENST00000394805.8	NP_061322.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MATR3	ENST00000394805.8 linkuse as main transcript	c.2521C>T	p.Arg841Cys	missense_variant	15/15	1	NM_018834.6	ENSP00000378284	P1	P43243-1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000136

AC:

AN:

250422

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135526

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000256

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000345

AC:

504

AN:

1459662

Hom.:

Cov.:

AF XY:

0.000289

AC XY:

210

AN XY:

726366

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000430

Gnomad4 OTH exome

AF:

0.000216

GnomAD4 genome

AF:

0.000204

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000263

Hom.:

Bravo

AF:

0.000212

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 21

Benign:2

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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 09, 2020

See Variant Classification Assertion Criteria. -

MATR3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 18, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.059

T;T;T;T;T;T;T;.;T;.

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.88

.;.;.;.;D;.;D;D;D;D

M_CAP

Benign

0.033

MetaRNN

Benign

0.12

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.81

L;L;.;.;.;L;.;.;L;.

MutationTaster

Benign

0.94

D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.84

N;N;N;N;N;N;N;N;.;.

REVEL

Benign

0.10

Sift

Uncertain

0.020

D;D;D;D;D;D;D;D;.;.

Sift4G

Benign

0.12

T;T;.;T;T;T;.;T;T;T

Polyphen

0.73

P;P;.;D;D;P;.;.;P;.

Vest4

0.29

MVP

0.77

MPC

0.24

ClinPred

0.079

GERP RS

4.5

Varity_R

0.10

gMVP

0.41

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

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