rs12153162

Variant names:

• chr5-139307373-T-A
• rs12153162
• NM_018834.6:c.-43T>A

Your query was ambiguous. Multiple possible variants found:

• chr5-139307373-T-A
• chr5-139307373-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018834.6(MATR3):​c.-43T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 1,507,718 control chromosomes in the GnomAD database, including 369,403 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (27398 hom., cov: 30)
  • Exomes 𝑓: 0.71 (342005 hom.)
• Consequence: MATR3 NM_018834.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.64
• Publications: 13 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=-0.88).
• BP6: Variant 5-139307373-T-A is Benign according to our data. Variant chr5-139307373-T-A is described in ClinVar as Benign. ClinVar VariationId is 263207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MATR3	NM_018834.6	c.-43T>A		5_prime_UTR_variant	Exon 2 of 15	ENST00000394805.8	NP_061322.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MATR3	ENST00000394805.8	c.-43T>A		5_prime_UTR_variant	Exon 2 of 15	1	NM_018834.6	ENSP00000378284.3
MATR3	ENST00000502929.5	c.-43T>A		5_prime_UTR_variant	Exon 7 of 20	2		ENSP00000422319.1

Frequencies

GnomAD3 genomes AF: 0.568 AC: 85669 AN: 150886 Hom.: 27400 Cov.: 30

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.647

Gnomad NFE AF: 0.732

Gnomad OTH AF: 0.597

GnomAD2 exomes AF: 0.675 AC: 128217 AN: 189950 AF XY: 0.684

Gnomad AFR exome AF: 0.330

Gnomad AMR exome AF: 0.703

Gnomad ASJ exome AF: 0.726

Gnomad EAS exome AF: 0.314

Gnomad FIN exome AF: 0.684

Gnomad NFE exome AF: 0.738

Gnomad OTH exome AF: 0.699

GnomAD4 exome AF: 0.713 AC: 966915 AN: 1356720 Hom.: 342005 Cov.: 40 AF XY: 0.714 AC XY: 481010 AN XY: 673782

African (AFR) AF: 0.298 AC: 7996 AN: 26822

American (AMR) AF: 0.682 AC: 22041 AN: 32332

Ashkenazi Jewish (ASJ) AF: 0.717 AC: 16520 AN: 23034

East Asian (EAS) AF: 0.331 AC: 11002 AN: 33214

South Asian (SAS) AF: 0.694 AC: 50450 AN: 72700

European-Finnish (FIN) AF: 0.679 AC: 33223 AN: 48900

Middle Eastern (MID) AF: 0.689 AC: 3512 AN: 5098

European-Non Finnish (NFE) AF: 0.741 AC: 784704 AN: 1059112

Other (OTH) AF: 0.675 AC: 37467 AN: 55508

GnomAD4 genome AF: 0.567 AC: 85687 AN: 150998 Hom.: 27398 Cov.: 30 AF XY: 0.563 AC XY: 41482 AN XY: 73706

African (AFR) AF: 0.274 AC: 11243 AN: 41056

American (AMR) AF: 0.609 AC: 9225 AN: 15140

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 2434 AN: 3454

East Asian (EAS) AF: 0.247 AC: 1266 AN: 5124

South Asian (SAS) AF: 0.656 AC: 3145 AN: 4792

European-Finnish (FIN) AF: 0.660 AC: 6845 AN: 10378

Middle Eastern (MID) AF: 0.647 AC: 189 AN: 292

European-Non Finnish (NFE) AF: 0.732 AC: 49567 AN: 67760

Other (OTH) AF: 0.596 AC: 1248 AN: 2094

Alfa AF: 0.510 Hom.: 1379

Bravo AF: 0.548

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Amyotrophic lateral sclerosis type 21 Benign:1

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. -

not provided Benign:1

Aug 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.073
DANN	Benign	0.64
PhyloP100		-1.6
Mutation Taster		=119/181	disease causing (long InDel)

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

Other links and lift over

dbSNP: rs12153162; hg19: chr5-138643062; COSMIC: COSV63075947; COSMIC: COSV63075947;