chr21-44521921-G-A

Position:

chr21-44521921-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_144991.3(TSPEAR):c.1528C>T(p.Arg510Ter) 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:4U:2

Conservation

PhyloP100: 2.32

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-AS2 (HGNC:16428): (TSPEAR antisense RNA 2)

TSPEAR-AS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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 21-44521921-G-A is Pathogenic according to our data. Variant chr21-44521921-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504870.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPEAR	NM_144991.3 linkuse as main transcript	c.1528C>T	p.Arg510Ter	stop_gained	9/12	ENST00000323084.9
TSPEAR	NM_001272037.2 linkuse as main transcript	c.1324C>T	p.Arg442Ter	stop_gained	10/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPEAR	ENST00000323084.9 linkuse as main transcript	c.1528C>T	p.Arg510Ter	stop_gained	9/12	1	NM_144991.3	P1	Q8WU66-1
TSPEAR	ENST00000397916.1 linkuse as main transcript	n.1483C>T		non_coding_transcript_exon_variant	9/11	1
TSPEAR-AS2	ENST00000465978.1 linkuse as main transcript	n.217-3903G>A		intron_variant, non_coding_transcript_variant		5
TSPEAR	ENST00000642437.1 linkuse as main transcript	c.*1473C>T		3_prime_UTR_variant, NMD_transcript_variant	10/13

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

GnomAD3 exomes

AF:

0.000342

AC:

AN:

251220

Hom.:

AF XY:

0.000390

AC XY:

AN XY:

135828

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 SAS exome

AF:

0.0000327

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

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000206

Gnomad4 NFE exome

AF:

0.000309

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000131

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000210

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:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 11, 2020	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 -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 21, 2023

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; Invitae). 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

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 20, 2022

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 02, 2017

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.042

FATHMM_MKL

Benign

0.19

MutationTaster

Benign

1.0

A;A

Vest4

0.15

GERP RS

-0.21

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

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