5-139307500-C-T

Position:

• chr5-139307500-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_018834.6(MATR3):​c.85C>T​(p.Leu29Phe) variant causes a missense change. 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MATR3 NM_018834.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.68

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 2 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=0.35434085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MATR3	NM_018834.6	c.85C>T	p.Leu29Phe	missense_variant	2/15	ENST00000394805.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MATR3	ENST00000394805.8	c.85C>T	p.Leu29Phe	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

Nov 27, 2023

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 29 of the MATR3 protein (p.Leu29Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of distal myopathy (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1036304). 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 tolerated. 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	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	T;T;.;T;T;T;.;T;.;T;T;.;.;T;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	0.55	N;N;.;.;.;.;.;N;.;.;N;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.37	N;N;D;N;N;D;D;N;N;N;.;D;D;D;D;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;T
Polyphen		1.0	D;D;.;P;P;.;.;D;.;D;D;.;.;.;.;.
Vest4		0.53
MutPred		0.27		Loss of glycosylation at T33 (P = 0.0924);Loss of glycosylation at T33 (P = 0.0924);Loss of glycosylation at T33 (P = 0.0924);Loss of glycosylation at T33 (P = 0.0924);Loss of glycosylation at T33 (P = 0.0924);Loss of glycosylation at T33 (P = 0.0924);Loss of glycosylation at T33 (P = 0.0924);Loss of glycosylation at T33 (P = 0.0924);Loss of glycosylation at T33 (P = 0.0924);Loss of glycosylation at T33 (P = 0.0924);Loss of glycosylation at T33 (P = 0.0924);Loss of glycosylation at T33 (P = 0.0924);Loss of glycosylation at T33 (P = 0.0924);Loss of glycosylation at T33 (P = 0.0924);Loss of glycosylation at T33 (P = 0.0924);Loss of glycosylation at T33 (P = 0.0924);
MVP		0.75
MPC		1.5
ClinPred		0.59	D
GERP RS		5.8
Varity_R		0.32
gMVP		0.64

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: rs1754770320; hg19: chr5-138643189;