rs1554146560

Positions:

• chr5-139308208-C-A
• chr5-139308208-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_018834.6(MATR3):​c.793C>A​(p.Leu265Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. L265L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MATR3 NM_018834.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.99

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MATR3
• BP4: Computational evidence support a benign effect (MetaRNN=0.26149684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MATR3	NM_018834.6	c.793C>A	p.Leu265Ile	missense_variant	2/15	ENST00000394805.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MATR3	ENST00000394805.8	c.793C>A	p.Leu265Ile	missense_variant	2/15	1	NM_018834.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 09, 2017

This sequence change replaces leucine with isoleucine at codon 265 of the MATR3 protein (p.Leu265Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MATR3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	35
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	T;T;T;T;T;.;T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.070	D
MutationAssessor	Benign	0.76	N;N;.;.;N;.;.;N
MutationTaster	Benign	0.94	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.82	N;N;N;N;N;N;N;.
REVEL	Benign	0.27
Sift	Uncertain	0.013	D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.045	D;D;D;D;D;T;D;D
Polyphen		1.0	D;D;P;P;D;.;D;D
Vest4		0.34
MutPred		0.15		Gain of methylation at K269 (P = 0.0621);Gain of methylation at K269 (P = 0.0621);Gain of methylation at K269 (P = 0.0621);Gain of methylation at K269 (P = 0.0621);Gain of methylation at K269 (P = 0.0621);Gain of methylation at K269 (P = 0.0621);Gain of methylation at K269 (P = 0.0621);Gain of methylation at K269 (P = 0.0621);
MVP		0.68
MPC		2.1
ClinPred		0.50	T
GERP RS		5.4
Varity_R		0.27
gMVP		0.29

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: rs1554146560; hg19: chr5-138643897;