5-139294029-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PVS1_ModeratePP3BS2

The ENST00000618441.5(MATR3):c.-178+1G>T variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000797 in 1,279,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

MATR3
ENST00000618441.5 splice_donor

Scores

Splicing: ADA: 0.9745

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.55

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PVS1

Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.09827044 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.1, offset of 45, new splice context is: aggGTgcgg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BS2

High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MATR3	NM_018834.6 linkuse as main transcript	c.-178+224G>T		intron_variant		ENST00000394805.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MATR3	ENST00000394805.8 linkuse as main transcript	c.-178+224G>T		intron_variant		1	NM_018834.6	P1	P43243-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000272

AC:

AN:

18378

Hom.:

AF XY:

0.000281

AC XY:

AN XY:

10678

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000580

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000781

AC:

AN:

1127018

Hom.:

Cov.:

AF XY:

0.0000722

AC XY:

AN XY:

540356

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000904

Gnomad4 OTH exome

AF:

0.0000659

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000574

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

MATR3-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 15, 2023

The MATR3 c.48+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in one sporadic amyotrophic lateral sclerosis case and has been shown to alter splicing (Leblond et al. 2016. PubMed ID: 26493020). However other isoforms of this gene do not utilize this splice site. This variant is reported in 0.025% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-138629718-G-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.21

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Benign

0.35

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

ClinPred

0.29

GERP RS

4.9

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.74

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over