Genetic Variant MATR3:c.-177-90delT (chr5-139307139-GT-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_018834.6(MATR3):c.-177-90delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 784,646 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00090 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 0 hom. )

Consequence

MATR3
NM_018834.6 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.379

Publications

0 publications found

Variant links:

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):

distal myopathy with vocal cord weakness
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
amyotrophic lateral sclerosis type 21
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MATR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 133 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018834.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MATR3	NM_018834.6	MANE Select	c.-177-90delT	intron	N/A	NP_061322.2
MATR3	NM_001400441.1		c.-177-90delT	intron	N/A	NP_001387370.1	A8MXP9
MATR3	NM_001400442.1		c.-177-90delT	intron	N/A	NP_001387371.1	A8MXP9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MATR3	ENST00000394805.8	TSL:1 MANE Select	c.-177-90delT	intron	N/A	ENSP00000378284.3	P43243-1
MATR3	ENST00000502929.5	TSL:2	c.-177-90delT	intron	N/A	ENSP00000422319.1	A8MXP9
MATR3	ENST00000618441.5	TSL:1	c.-177-90delT	intron	N/A	ENSP00000482895.1	P43243-1

Frequencies

GnomAD3 genomes

AF:

0.000903

AC:

133

AN:

147256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00254

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000136

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000645

Gnomad FIN

AF:

0.000104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000346

Gnomad OTH

AF:

0.000990

GnomAD4 exome

AF:

0.00416

AC:

2650

AN:

637286

Hom.:

AF XY:

0.00418

AC XY:

1277

AN XY:

305650

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00734

AC:

AN:

13216

American (AMR)

AF:

0.00661

AC:

AN:

5752

Ashkenazi Jewish (ASJ)

AF:

0.00400

AC:

AN:

7750

East Asian (EAS)

AF:

0.00630

AC:

AN:

10956

South Asian (SAS)

AF:

0.00466

AC:

AN:

17604

European-Finnish (FIN)

AF:

0.00688

AC:

AN:

6688

Middle Eastern (MID)

AF:

0.00490

AC:

AN:

1632

European-Non Finnish (NFE)

AF:

0.00396

AC:

2175

AN:

548782

Other (OTH)

AF:

0.00418

AC:

104

AN:

24906

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.257

Heterozygous variant carriers

409

818

1226

1635

2044

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

188

282

376

470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000903

AC:

133

AN:

147360

Hom.:

Cov.:

AF XY:

0.000934

AC XY:

AN XY:

71764

show subpopulations

African (AFR)

AF:

0.00254

AC:

102

AN:

40208

American (AMR)

AF:

0.000136

AC:

AN:

14706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3384

East Asian (EAS)

AF:

0.00

AC:

AN:

5054

South Asian (SAS)

AF:

0.000646

AC:

AN:

4642

European-Finnish (FIN)

AF:

0.000104

AC:

AN:

9598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.000346

AC:

AN:

66548

Other (OTH)

AF:

0.000981

AC:

AN:

2038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000143

Hom.:

Bravo

AF:

0.000907

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.38

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

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5-139307139-GTTTTT-GTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over