chr21-44499878-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_144991.3(TSPEAR):c.1915G>A(p.Asp639Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00379 in 1,606,932 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0039 ( 18 hom. )

Consequence

TSPEAR
NM_144991.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:6B:5

Conservation

PhyloP100: 7.10

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012871683).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00228 (348/152346) while in subpopulation NFE AF= 0.00363 (247/68030). AF 95% confidence interval is 0.00326. There are 1 homozygotes in gnomad4. There are 153 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPEAR	NM_144991.3 link	c.1915G>A	p.Asp639Asn	missense_variant	Exon 12 of 12	ENST00000323084.9	NP_659428.2	Q8WU66-1
TSPEAR	NM_001272037.2 link	c.1711G>A	p.Asp571Asn	missense_variant	Exon 13 of 13		NP_001258966.1	Q8WU66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TSPEAR	ENST00000323084.9 link	c.1915G>A	p.Asp639Asn	missense_variant	Exon 12 of 12	1	NM_144991.3	ENSP00000321987.4	Q8WU66-1
TSPEAR	ENST00000642437.1 link	n.*1860G>A		non_coding_transcript_exon_variant	Exon 13 of 13			ENSP00000496535.1	A0A2R8YFK6
TSPEAR	ENST00000642437.1 link	n.*1860G>A		3_prime_UTR_variant	Exon 13 of 13			ENSP00000496535.1	A0A2R8YFK6

Frequencies

GnomAD3 genomes

AF:

0.00229

AC:

348

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00235

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00363

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00229

AC:

533

AN:

232456

Hom.:

AF XY:

0.00231

AC XY:

295

AN XY:

127430

show subpopulations

Gnomad AFR exome

AF:

0.000698

Gnomad AMR exome

AF:

0.00214

Gnomad ASJ exome

AF:

0.00532

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000341

Gnomad FIN exome

AF:

0.000608

Gnomad NFE exome

AF:

0.00360

Gnomad OTH exome

AF:

0.00299

GnomAD4 exome

AF:

0.00394

AC:

5738

AN:

1454586

Hom.:

Cov.:

AF XY:

0.00379

AC XY:

2743

AN XY:

723268

show subpopulations

Gnomad4 AFR exome

AF:

0.000633

Gnomad4 AMR exome

AF:

0.00244

Gnomad4 ASJ exome

AF:

0.00483

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000940

Gnomad4 FIN exome

AF:

0.000968

Gnomad4 NFE exome

AF:

0.00473

Gnomad4 OTH exome

AF:

0.00286

GnomAD4 genome

AF:

0.00228

AC:

348

AN:

152346

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

153

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000577

Gnomad4 AMR

AF:

0.00235

Gnomad4 ASJ

AF:

0.00662

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.00363

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00328

Hom.:

Bravo

AF:

0.00239

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000912

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00217

AC:

262

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:6Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TSPEAR: BS2 -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 06, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30046887, 27736875, 34042254, 25855803, 33144682, 37853563, 37009414) -

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

Pathogenic:3Uncertain:1

Aug 03, 2022

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (G>A) at coding nucleotide 1915 in the TSPEAR gene which results in an aspartic acid to asparagine amino acid change at residue 639 in the TSPEAR protein. This is a previously reported variant (ClinVar) which has been reported with a second variant in compound heterozygous state in multiple individuals with ectodermal dysplasia with tooth agenesis (PMID: 34042254, 27736875). The variant is present in 594/263832 alleles, including 1 homozygote, in the gnomAD control population dataset. Multiple bioinformatic tools predict that this variant is likely to be damaging, and aspartic acid is highly conserved at this protein position in vertebrates. Functiol studies testing the effects of this variant have not been performed, to our knowledge. Based on the available evidence, we consider this variant to be likely pathogenic; however, based on the presence of a homozygous individual in a control dataset, it may represent an allele which requires a stronger loss of function allele on the opposite chromosome for disease phenotypes to manifest. ACMG Criteria: PM3, PP3, PP4, PS4 -

Apr 20, 2023

Duke University Health System Sequencing Clinic, Duke University Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Dec 05, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 20, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with tooth agenesis, selective, 10 (MIM#620173) and ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis (MIM#618180). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (592 heterozygotes, 1 homozygote). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as benign, likely benign, a VUS and pathogenic by clinical laboratories in ClinVar. The variant has also been observed as compound heterozygous or homozygous in eight families with hypodontia and ectodermal dysplasia in the literature, and was classified as a VUS or as likely pathogenic (PMID: 34042254, 27736875, 37009414). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Tooth agenesis, selective, 10

Pathogenic:1Uncertain:1

Nov 24, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 20, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases

Uncertain:1

Aug 16, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 98

Uncertain:1

Jan 18, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Benign:1

Jan 07, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asp639Asn in exon 12 of TSPEAR: This variant is not expected to have clinical significance because it has been identified in 0.5% (214/39556) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs138480801). -

TSPEAR-related disorder

Benign:1

Aug 24, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.31

T;T

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.96

.;D

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.6

.;D

REVEL

Benign

0.28

Sift

Uncertain

0.025

.;D

Sift4G

Pathogenic

0.0

.;D

Polyphen

1.0

D;D

Vest4

0.64

MVP

0.30

MPC

0.33

ClinPred

0.022

GERP RS

4.3

Varity_R

0.42

gMVP

0.66

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