rs147239107

chr5-139307706-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_018834.6(MATR3):c.291A>G(p.Leu97=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 1,614,108 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: MATR3 NM_018834.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.88

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 5-139307706-A-G is Benign according to our data. Variant chr5-139307706-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 351121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.88 with no splicing effect.
• BS2: High AC in GnomAd at 53 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MATR3	NM_018834.6	c.291A>G	p.Leu97=	synonymous_variant	2/15	ENST00000394805.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MATR3	ENST00000394805.8	c.291A>G	p.Leu97=	synonymous_variant	2/15	1	NM_018834.6	P1

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000466 AC: 117 AN: 251276 Hom.: 1 AF XY: 0.000390 AC XY: 53 AN XY: 135820

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.000273 AC: 399 AN: 1461828 Hom.: 1 Cov.: 34 AF XY: 0.000289 AC XY: 210 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000249

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74452

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000677 Hom.: 1

Bravo AF: 0.000476

EpiCase AF: 0.000164

EpiControl AF: 0.000711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 21 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 17, 2020

- -

MATR3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	12
Dann	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs147239107; hg19: chr5-138643395; COSMIC: COSV63075468; COSMIC: COSV63075468;