21-44509275-CAT-C

Position:

chr21-44509275-CAT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_144991.3(TSPEAR):c.1676_1677del(p.Tyr559CysfsTer134) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

TSPEAR
NM_144991.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.24

Variant links:

Genes affected

TSPEAR (HGNC:1268): (thrombospondin type laminin G domain and EAR repeats) This gene encodes a protein that contains a N-terminal thrombospondin-type laminin G domain and several tandem arranged epilepsy-associated repeats (EARs). A mutation in this gene is the cause of autosomal recessive deafness-98. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

TSPEAR links:

TSPEAR-AS1 (HGNC:1271): (TSPEAR antisense RNA 1)

TSPEAR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 21-44509275-CAT-C is Pathogenic according to our data. Variant chr21-44509275-CAT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 817061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44509275-CAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TSPEAR	NM_144991.3 linkuse as main transcript	c.1676_1677del	p.Tyr559CysfsTer134	frameshift_variant	10/12	ENST00000323084.9	NP_659428.2
TSPEAR-AS1	NR_103707.1 linkuse as main transcript	n.1240_1241del		non_coding_transcript_exon_variant	5/7
TSPEAR	NM_001272037.2 linkuse as main transcript	c.1472_1473del	p.Tyr491CysfsTer134	frameshift_variant	11/13		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9 linkuse as main transcript	c.1676_1677del	p.Tyr559CysfsTer134	frameshift_variant	10/12	1	NM_144991.3	ENSP00000321987	P1	Q8WU66-1
TSPEAR	ENST00000397916.1 linkuse as main transcript	n.1631_1632del		non_coding_transcript_exon_variant	10/11	1
TSPEAR-AS1	ENST00000451035.2 linkuse as main transcript	n.795_796del		non_coding_transcript_exon_variant	4/6	5
TSPEAR	ENST00000642437.1 linkuse as main transcript	c.1621_1622del		3_prime_UTR_variant, NMD_transcript_variant	11/13			ENSP00000496535

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251348

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135880

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:

0.0000968

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000493

AC:

AN:

1461856

Hom.:

AF XY:

0.0000413

AC XY:

AN XY:

727232

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:

0.0000620

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000882

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 10, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TSPEAR protein in which other variant(s) (p.Val576Leufs38) have been determined to be pathogenic (PMID: 27736875, 30046887). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 817061). This variant is also known as c.1472_1473delAT. This frameshift has been observed in individual(s) with deafness (PMID: 34042254). This variant is present in population databases (rs781890406, gnomAD 0.01%). This sequence change results in a frameshift in the TSPEAR gene (p.Tyr559Cysfs134). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 111 amino acid(s) of the TSPEAR protein and extend the protein by 22 additional amino acid residues. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2024	Frameshift variant predicted to result in abnormal protein length as the last 111 amino acid(s) are replaced with 133 different amino acid(s), and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 34042254, 26969326) -

TSPEAR-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2024

The TSPEAR c.1676_1677delAT variant is predicted to result in a frameshift and premature protein termination (p.Tyr559Cysfs*134). This variant was reported, along with another variant in TSPEAR in an individual with Hearing loss (reported as c.1472_1473delAT in Sloan-Heggen et al. 2016. PubMed ID: 26969326). This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in TSPEAR are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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