rs752161415

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The ENST00000394805.8(MATR3):c.2038G>A(p.Asp680Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000743 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D680H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

MATR3
ENST00000394805.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.65

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 Likely_benign. Variant got -4 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=0.32343638).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MATR3	NM_018834.6 linkuse as main transcript	c.2038G>A	p.Asp680Asn	missense_variant	12/15	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.2038G>A	p.Asp680Asn	missense_variant	12/15	1	NM_018834.6	ENSP00000378284	P1	P43243-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251370

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 21

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	May 21, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 680 of the MATR3 protein (p.Asp680Asn). This variant is present in population databases (rs752161415, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with MATR3-related conditions. ClinVar contains an entry for this variant (Variation ID: 474081). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2023

The c.2038G>A (p.D680N) alteration is located in exon 15 (coding exon 11) of the MATR3 gene. This alteration results from a G to A substitution at nucleotide position 2038, causing the aspartic acid (D) at amino acid position 680 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.077

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

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

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

M_CAP

Benign

0.022

MetaRNN

Benign

0.32

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

MetaSVM

Uncertain

0.069

MutationAssessor

Benign

0.97

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.0

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

REVEL

Uncertain

0.29

Sift

Benign

0.091

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

Sift4G

Benign

0.11

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

Polyphen

0.99

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

Vest4

0.29

MutPred

0.30

Gain of loop (P = 0.069);Gain of loop (P = 0.069);.;Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);.;Gain of loop (P = 0.069);.;Gain of loop (P = 0.069);.;

MVP

0.81

MPC

0.52

ClinPred

0.83

GERP RS

5.4

Varity_R

0.17

gMVP

0.19

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