rs587777302

Positions:

chr5-139307875-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The ENST00000394805.8(MATR3):c.460C>T(p.Pro154Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P154P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MATR3
ENST00000394805.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 1.95

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.20779598).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MATR3	NM_018834.6 linkuse as main transcript	c.460C>T	p.Pro154Ser	missense_variant	2/15	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.460C>T	p.Pro154Ser	missense_variant	2/15	1	NM_018834.6	ENSP00000378284	P1	P43243-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152002

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 21

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 18, 2023	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 154 of the MATR3 protein (p.Pro154Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 24686783). ClinVar contains an entry for this variant (Variation ID: 126563). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MATR3 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 30, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.063

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

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.82

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

M_CAP

Benign

0.030

MetaRNN

Benign

0.21

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

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

1.4

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

MutationTaster

Benign

0.89

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

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.6

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

REVEL

Benign

0.14

Sift

Benign

0.062

T;T;T;T;T;T;D;.

Sift4G

Benign

0.22

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

Polyphen

0.0010

B;B;D;D;B;.;B;B

Vest4

0.16

MutPred

0.18

Gain of phosphorylation at P154 (P = 0.0183);Gain of phosphorylation at P154 (P = 0.0183);Gain of phosphorylation at P154 (P = 0.0183);Gain of phosphorylation at P154 (P = 0.0183);Gain of phosphorylation at P154 (P = 0.0183);Gain of phosphorylation at P154 (P = 0.0183);Gain of phosphorylation at P154 (P = 0.0183);Gain of phosphorylation at P154 (P = 0.0183);

MVP

0.82

MPC

0.94

ClinPred

0.28

GERP RS

4.7

Varity_R

0.10

gMVP

0.42

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