rs1033118784

Variant names:

• chr5-139319497-G-A
• rs1033118784
• NM_018834.6:c.1598G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_018834.6(MATR3):​c.1598G>A​(p.Ser533Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000219 in 1,460,226 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: MATR3 NM_018834.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.14

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity MATR3_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.18239191).
• BS2: High AC in GnomAdExome4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MATR3	NM_018834.6	c.1598G>A	p.Ser533Asn	missense_variant	Exon 9 of 15	ENST00000394805.8	NP_061322.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MATR3	ENST00000394805.8	c.1598G>A	p.Ser533Asn	missense_variant	Exon 9 of 15	1	NM_018834.6	ENSP00000378284.3
MATR3	ENST00000394800.6	c.1598G>A	p.Ser533Asn	missense_variant	Exon 13 of 19	5		ENSP00000378279.2
MATR3	ENST00000502929.5	c.1598G>A	p.Ser533Asn	missense_variant	Exon 14 of 20	2		ENSP00000422319.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1460226 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 726516

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis type 21 Uncertain:1

May 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 533 of the MATR3 protein (p.Ser533Asn). This variant is not present in population databases (gnomAD no frequency). 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: 578420). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	23
DANN	Benign	0.92
DEOGEN2	Benign	0.037	T;T;T;T;T;T;T;T;.;T
Eigen	Benign	0.0097
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	.;.;.;.;T;.;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.4	N;N;.;.;.;N;.;.;.;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.43	N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.18
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.59	T;T;.;T;T;T;.;T;T;T
Polyphen		0.025	B;B;.;P;P;B;.;B;.;B
Vest4		0.38
MutPred		0.48		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);.;Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);.;Loss of sheet (P = 0.0457);.;Loss of sheet (P = 0.0457);
MVP		0.74
MPC		2.0
ClinPred		0.87	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.71

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

Other links and lift over

dbSNP: rs1033118784; hg19: chr5-138655186;