rs80036770

Variant names:

• chr5-139319507-A-G
• rs80036770
• NM_018834.6:c.1602+6A>G

Variant summary

Our verdict is Benign. The variant received -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 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.00002836
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.742
• Publications: 3 publications found

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]

MATR3 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 21

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• distal myopathy with vocal cord weakness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 263208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2148 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MATR3	NM_018834.6	c.1602+6A>G		splice_region_variant, intron_variant	Intron 9 of 14	ENST00000394805.8	NP_061322.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MATR3	ENST00000394805.8	c.1602+6A>G		splice_region_variant, intron_variant	Intron 9 of 14	1	NM_018834.6	ENSP00000378284.3
MATR3	ENST00000502929.5	c.1602+6A>G		splice_region_variant, intron_variant	Intron 14 of 19	2		ENSP00000422319.1

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

GnomAD2 exomes AF: 0.0141 AC: 3537 AN: 250350 AF XY: 0.0145

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 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

African (AFR) AF: 0.00373 AC: 124 AN: 33266

American (AMR) AF: 0.00978 AC: 434 AN: 44386

Ashkenazi Jewish (ASJ) AF: 0.00631 AC: 162 AN: 25670

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39634

South Asian (SAS) AF: 0.0102 AC: 878 AN: 85694

European-Finnish (FIN) AF: 0.0136 AC: 725 AN: 53286

Middle Eastern (MID) AF: 0.00666 AC: 34 AN: 5102

European-Non Finnish (NFE) AF: 0.0264 AC: 28995 AN: 1100182

Other (OTH) AF: 0.0215 AC: 1285 AN: 59758

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

African (AFR) AF: 0.00416 AC: 173 AN: 41556

American (AMR) AF: 0.0130 AC: 199 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00637 AC: 22 AN: 3456

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00956 AC: 46 AN: 4812

European-Finnish (FIN) AF: 0.00943 AC: 100 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0233 AC: 1579 AN: 67902

Other (OTH) AF: 0.0123 AC: 26 AN: 2110

Alfa AF: 0.0191 Hom.: 64

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Nov 11, 2016

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Amyotrophic lateral sclerosis type 21 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Aug 26, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.7
DANN	Benign	0.66
PhyloP100		0.74
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs80036770; hg19: chr5-138655196;