rs121434591

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_018834.6(MATR3):c.254C>G(p.Ser85Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

MATR3
NM_018834.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 5.68

Publications

64 publications found

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 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis type 21
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
distal myopathy with vocal cord weakness
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MATR3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.86

PP5

Variant 5-139307669-C-G is Pathogenic according to our data. Variant chr5-139307669-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 14002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MATR3	NM_018834.6 link	c.254C>G	p.Ser85Cys	missense_variant	Exon 2 of 15	ENST00000394805.8	NP_061322.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MATR3	ENST00000394805.8 link	c.254C>G	p.Ser85Cys	missense_variant	Exon 2 of 15	1	NM_018834.6	ENSP00000378284.3
MATR3	ENST00000502929.5 link	c.254C>G	p.Ser85Cys	missense_variant	Exon 7 of 20	2		ENSP00000422319.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 21

Pathogenic:5

Dec 12, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 10, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

UniProtKB/Swiss-Prot

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 85 of the MATR3 protein (p.Ser85Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant distal myopathy with variable vocal cord weakness, pharyngeal weakness and respiratory failure (PMID: 9837826, 19344878, 24686783, 25154462, 25677933, 25952333). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14002). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MATR3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MATR3 function (PMID: 24686783). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Jun 20, 2017

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.095

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

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

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

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.86

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

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

0.55

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

PhyloP100

5.7

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.4

N;N;D;N;N;D;N;N;N;.;D;D

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.56

MutPred

0.77

Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);

MVP

0.90

MPC

2.0

ClinPred

0.74

GERP RS

5.8

PromoterAI

-0.00010

Neutral

(source)

Varity_R

0.34

gMVP

0.82

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over