rs80036770

Positions:

• chr5-139319507-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018834.6(MATR3):​c.1602+6A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0218 in 1,599,072 control chromosomes in the GnomAD database, including 482 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (24 hom., cov: 32)
  • Exomes 𝑓: 0.023 (458 hom.)
• Consequence: MATR3 NM_018834.6 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00002836
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.742

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-139319507-A-G is Benign according to our data. Variant chr5-139319507-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 263208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-139319507-A-G is described in Lovd as [Benign]. Variant chr5-139319507-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0141 (2148/152094) while in subpopulation NFE AF= 0.0233 (1579/67902). AF 95% confidence interval is 0.0223. There are 24 homozygotes in gnomad4. There are 964 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2148 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MATR3	NM_018834.6	c.1602+6A>G		splice_donor_region_variant, intron_variant		ENST00000394805.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MATR3	ENST00000394805.8	c.1602+6A>G		splice_donor_region_variant, intron_variant		1	NM_018834.6	P1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2148 AN: 151976 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00418

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.00637

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00934

Gnomad FIN AF: 0.00943

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0233

Gnomad OTH AF: 0.0125

GnomAD3 exomes AF: 0.0141 AC: 3537 AN: 250350 Hom.: 50 AF XY: 0.0145 AC XY: 1970 AN XY: 135536

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.00938

Gnomad ASJ exome AF: 0.00628

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00908

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.0215

Gnomad OTH exome AF: 0.0173

GnomAD4 exome AF: 0.0226 AC: 32642 AN: 1446978 Hom.: 458 Cov.: 30 AF XY: 0.0221 AC XY: 15892 AN XY: 720340

Gnomad4 AFR exome AF: 0.00373

Gnomad4 AMR exome AF: 0.00978

Gnomad4 ASJ exome AF: 0.00631

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0102

Gnomad4 FIN exome AF: 0.0136

Gnomad4 NFE exome AF: 0.0264

Gnomad4 OTH exome AF: 0.0215

GnomAD4 genome AF: 0.0141 AC: 2148 AN: 152094 Hom.: 24 Cov.: 32 AF XY: 0.0130 AC XY: 964 AN XY: 74388

Gnomad4 AFR AF: 0.00416

Gnomad4 AMR AF: 0.0130

Gnomad4 ASJ AF: 0.00637

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00956

Gnomad4 FIN AF: 0.00943

Gnomad4 NFE AF: 0.0233

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0163 Hom.: 22

Bravo AF: 0.0143

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0207

EpiControl AF: 0.0209

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 11, 2016	- -

Amyotrophic lateral sclerosis type 21 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 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

Aug 26, 2019

This variant is associated with the following publications: (PMID: 26493020) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.7
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0
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: rs80036770; hg19: chr5-138655196;