5-139307455-T-C

Variant names:

• chr5-139307455-T-C
• rs760526286
• NM_018834.6:c.40T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_018834.6(MATR3):​c.40T>C​(p.Ser14Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,824 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MATR3 NM_018834.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity MATR3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12183586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MATR3	NM_018834.6	c.40T>C	p.Ser14Pro	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	c.40T>C	p.Ser14Pro	missense_variant	Exon 2 of 15	1	NM_018834.6	ENSP00000378284.3
MATR3	ENST00000394800.6	c.40T>C	p.Ser14Pro	missense_variant	Exon 6 of 19	5		ENSP00000378279.2
MATR3	ENST00000502929.5	c.40T>C	p.Ser14Pro	missense_variant	Exon 7 of 20	2		ENSP00000422319.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250858 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135624

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461824 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis type 21 Uncertain:1

Jun 12, 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 proline, which is neutral and non-polar, at codon 14 of the MATR3 protein (p.Ser14Pro). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MATR3-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	Benign	0.17
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.038	T;T;.;T;T;T;.;T;.;T;T;.;.;T;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.79	.;.;T;.;T;T;T;.;T;T;T;T;T;T;T;D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	-0.34	N;N;.;.;.;.;.;N;.;.;N;.;.;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	1.1	N;N;D;N;N;D;D;N;N;N;.;D;D;D;D;.
REVEL	Benign	0.28
Sift	Benign	0.052	T;T;T;T;T;T;T;T;T;D;.;T;T;T;T;.
Sift4G	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.44	B;B;.;B;B;.;.;B;.;B;B;.;.;.;.;.
Vest4		0.37
MutPred		0.15		Loss of phosphorylation at S14 (P = 0.0069);Loss of phosphorylation at S14 (P = 0.0069);Loss of phosphorylation at S14 (P = 0.0069);Loss of phosphorylation at S14 (P = 0.0069);Loss of phosphorylation at S14 (P = 0.0069);Loss of phosphorylation at S14 (P = 0.0069);Loss of phosphorylation at S14 (P = 0.0069);Loss of phosphorylation at S14 (P = 0.0069);Loss of phosphorylation at S14 (P = 0.0069);Loss of phosphorylation at S14 (P = 0.0069);Loss of phosphorylation at S14 (P = 0.0069);Loss of phosphorylation at S14 (P = 0.0069);Loss of phosphorylation at S14 (P = 0.0069);Loss of phosphorylation at S14 (P = 0.0069);Loss of phosphorylation at S14 (P = 0.0069);Loss of phosphorylation at S14 (P = 0.0069);
MVP		0.80
MPC		2.0
ClinPred		0.17	T
GERP RS		4.6
Varity_R		0.16
gMVP		0.53

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: rs760526286; hg19: chr5-138643144;