5-139307471-G-A

Variant summary

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

The NM_018834.6(MATR3):c.56G>A(p.Arg19His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,842 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MATR3 NM_018834.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.86

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]

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=0.32991564).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MATR3	NM_018834.6	c.56G>A	p.Arg19His	missense_variant	2/15	ENST00000394805.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MATR3	ENST00000394805.8	c.56G>A	p.Arg19His	missense_variant	2/15	1	NM_018834.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250910 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135656

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461842 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2023

The c.56G>A (p.R19H) alteration is located in exon 5 (coding exon 1) of the MATR3 gene. This alteration results from a G to A substitution at nucleotide position 56, causing the arginine (R) at amino acid position 19 to be replaced by a histidine (H). 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	0.22
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	35
Dann	Uncertain	1.0
DEOGEN2	Benign	0.050	T;T;.;T;T;T;.;T;.;T;T;.;.;T;.;.
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	0.55	N;N;.;.;.;.;.;N;.;.;N;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.29	N;N;D;N;N;D;D;N;N;N;.;D;D;D;D;.
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	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;D
Polyphen		1.0	D;D;.;D;D;.;.;D;.;D;D;.;.;.;.;.
Vest4		0.61
MutPred		0.16		Loss of methylation at R19 (P = 0.0396);Loss of methylation at R19 (P = 0.0396);Loss of methylation at R19 (P = 0.0396);Loss of methylation at R19 (P = 0.0396);Loss of methylation at R19 (P = 0.0396);Loss of methylation at R19 (P = 0.0396);Loss of methylation at R19 (P = 0.0396);Loss of methylation at R19 (P = 0.0396);Loss of methylation at R19 (P = 0.0396);Loss of methylation at R19 (P = 0.0396);Loss of methylation at R19 (P = 0.0396);Loss of methylation at R19 (P = 0.0396);Loss of methylation at R19 (P = 0.0396);Loss of methylation at R19 (P = 0.0396);Loss of methylation at R19 (P = 0.0396);Loss of methylation at R19 (P = 0.0396);
MVP		0.83
MPC		2.3
ClinPred		0.47	T
GERP RS		5.8
Varity_R		0.20
gMVP		0.38

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: rs757397034; hg19: chr5-138643160;