5-139307491-A-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.76A>G(p.Ile26Val) 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: 4.79

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=0.21655211).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MATR3	NM_018834.6	c.76A>G	p.Ile26Val	missense_variant	2/15	ENST00000394805.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MATR3	ENST00000394805.8	c.76A>G	p.Ile26Val	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

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.76A>G (p.I26V) alteration is located in exon 5 (coding exon 1) of the MATR3 gene. This alteration results from a A to G substitution at nucleotide position 76, causing the isoleucine (I) at amino acid position 26 to be replaced by a valine (V). 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	0.13
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.048	T;T;.;T;T;T;.;T;.;T;T;.;.;T;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.34	N;N;.;.;.;.;.;N;.;.;N;.;.;.;.;.
MutationTaster	Benign	0.97	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.24	N;N;N;N;N;N;N;N;N;N;.;N;N;N;N;.
REVEL	Uncertain	0.34
Sift	Benign	0.11	T;T;T;T;T;T;T;T;T;T;.;T;T;T;T;.
Sift4G	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.14	B;B;.;B;B;.;.;B;.;B;B;.;.;.;.;.
Vest4		0.37
MutPred		0.23		Loss of catalytic residue at A30 (P = 0.1458);Loss of catalytic residue at A30 (P = 0.1458);Loss of catalytic residue at A30 (P = 0.1458);Loss of catalytic residue at A30 (P = 0.1458);Loss of catalytic residue at A30 (P = 0.1458);Loss of catalytic residue at A30 (P = 0.1458);Loss of catalytic residue at A30 (P = 0.1458);Loss of catalytic residue at A30 (P = 0.1458);Loss of catalytic residue at A30 (P = 0.1458);Loss of catalytic residue at A30 (P = 0.1458);Loss of catalytic residue at A30 (P = 0.1458);Loss of catalytic residue at A30 (P = 0.1458);Loss of catalytic residue at A30 (P = 0.1458);Loss of catalytic residue at A30 (P = 0.1458);Loss of catalytic residue at A30 (P = 0.1458);Loss of catalytic residue at A30 (P = 0.1458);
MVP		0.72
MPC		0.82
ClinPred		0.26	T
GERP RS		5.6
Varity_R		0.089
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-138643180;