NM_144991.3:c.1528C>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_144991.3(TSPEAR):c.1528C>T(p.Arg510*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000246 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

TSPEAR
NM_144991.3 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:2

Conservation

PhyloP100: 2.32

Publications

6 publications found

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 was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

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

PP5

Variant 21-44521921-G-A is Pathogenic according to our data. Variant chr21-44521921-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 504870.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPEAR	NM_144991.3 link	c.1528C>T	p.Arg510*	stop_gained	Exon 9 of 12	ENST00000323084.9	NP_659428.2	Q8WU66-1
TSPEAR	NM_001272037.2 link	c.1324C>T	p.Arg442*	stop_gained	Exon 10 of 13		NP_001258966.1	Q8WU66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9 link	c.1528C>T	p.Arg510*	stop_gained	Exon 9 of 12	1	NM_144991.3	ENSP00000321987.4		Q8WU66-1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000342

AC:

AN:

251220

AF XY:

0.000390

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.000704

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000258

AC:

377

AN:

1461744

Hom.:

Cov.:

AF XY:

0.000260

AC XY:

189

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000206

AC:

AN:

53318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000309

AC:

344

AN:

1111984

Other (OTH)

AF:

0.000232

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000131

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41568

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.000310

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000527

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis

Pathogenic:3

Jan 05, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jun 11, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 9 of 12). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (92 heterozygotes, 0 homozygotes). (P) 0507 - Identified variant type is not compatible with in silico predictions of pathogenicity. (N) 0703 - Comparable variants have moderate previous evidence for pathogenicity (ClinVar; PMID:27736875). (P) 0803 - Low previous evidence of pathogenicity in unrelated individual(s). This variant has been reported as compound heterozygous in a patient with non-syndromic oligodontia (PMID:32112661). It has also been reported as a variant of uncertain significance in ClinVar. (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Jan 29, 2024

Clinical Genetics and Genomics, Karolinska University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TSPEAR-related disorder

Pathogenic:1

Sep 06, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TSPEAR c.1528C>T variant is predicted to result in premature protein termination (p.Arg510*). This variant was reported in the compound heterozygous state along with a missense variant in an individual with nonsyndromic oligodontia (Song et al. 2020. PubMed ID: 32112661). This variant is reported in 0.065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in TSPEAR are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg510*) in the TSPEAR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSPEAR are known to be pathogenic (PMID: 34042254). This variant is present in population databases (rs201663789, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with clinical features of ectodermal dysplasia and/or non-syndromic oligodontia (PMID: 32112661; internal data). ClinVar contains an entry for this variant (Variation ID: 504870). For these reasons, this variant has been classified as Pathogenic. -

Tooth agenesis, selective, 10

Pathogenic:1

Dec 20, 2022

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Uncertain:1

May 02, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg510X variant in TSPEAR has not been previously reported in individuals with hearing loss, but has been identified in 82/126654 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org; db SNP rs201663789). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This nonsense v ariant leads to a premature termination codon at position 510, which is predicte d to lead to a truncated or absent protein. Truncating variants have been previo usly reported in two probands with hearing loss and segregated in two affected s iblings in one family (Delmaghani 2012, Sloan-Heggen 2016). However, a recent st udy has also associated truncating variants in TSPEAR, including the same varian t previously reported by Delmaghani et al, with autosomal recessive ectodermal d ysplasia without hearing loss (Peled 2016). Therefore, additional information i s needed to determine the gene-disease association and the disease mechanism. In summary, because the gene-disease association is unclear, the clinical signific ance of this variant is uncertain. -

Inborn genetic diseases

Uncertain:1

Aug 16, 2018

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.042

FATHMM_MKL

Benign

0.19

PhyloP100

2.3

Vest4

0.15

GERP RS

-0.21

Mutation Taster

=7/193

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over