21-44499878-C-T

Variant names:

• chr21-44499878-C-T
• rs138480801
• NM_144991.3:c.1915G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:7 B:5
• Conservation: PhyloP100: 7.10
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive nonsyndromic hearing loss 98

  Inheritance: AR Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. 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	c.1915G>A	p.Asp639Asn	missense_variant	Exon 12 of 12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.1711G>A	p.Asp571Asn	missense_variant	Exon 13 of 13		NP_001258966.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 348 AN: 152228 Hom.: 1 Cov.: 33

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

GnomAD2 exomes AF: 0.00229 AC: 533 AN: 232456 AF XY: 0.00231

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 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.: 18 Cov.: 31 AF XY: 0.00379 AC XY: 2743 AN XY: 723268

African (AFR) AF: 0.000633 AC: 21 AN: 33150

American (AMR) AF: 0.00244 AC: 108 AN: 44190

Ashkenazi Jewish (ASJ) AF: 0.00483 AC: 125 AN: 25888

East Asian (EAS) AF: 0.00 AC: 0 AN: 39256

South Asian (SAS) AF: 0.0000940 AC: 8 AN: 85146

European-Finnish (FIN) AF: 0.000968 AC: 50 AN: 51666

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 0.00473 AC: 5254 AN: 1109620

Other (OTH) AF: 0.00286 AC: 172 AN: 60060

GnomAD4 genome AF: 0.00228 AC: 348 AN: 152346 Hom.: 1 Cov.: 33 AF XY: 0.00205 AC XY: 153 AN XY: 74496

African (AFR) AF: 0.000577 AC: 24 AN: 41570

American (AMR) AF: 0.00235 AC: 36 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00363 AC: 247 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00316 Hom.: 2

Bravo AF: 0.00239

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000912 AC: 4

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00217 AC: 262

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:7 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2 Benign:3

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

- -

-

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

- -

May 07, 2025

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) -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TSPEAR: BS2 -

Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis Pathogenic:3 Uncertain:1

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 -

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

- -

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 -

Tooth agenesis, selective, 10 Pathogenic:1 Uncertain: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

- -

not specified Uncertain:1 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). -

Jun 30, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TSPEAR c.1915G>A (p.Asp639Asn) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.0038 in 1606932 control chromosomes, predominantly at a frequency of 0.0047-0.005 within the Non-Finnish European and Ashkenazi-Jewish subpopulations in the gnomAD database, including 19 homozygotes. The observed variant frequency within control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in TSPEAR causing Ectodermal Dysplasia 14, Hair/tooth Type With Or Without Hypohidrosis phenotype. c.1915G>A has been observed in trans with likely pathogenic/pathogenic variants or in the homozygous state in several individual(s) affected with Ectodermal Dysplasia 14, Hair/tooth Type With Or Without Hypohidrosis (example, Bowles_2021, Labcorp Genetics (formerly Invitae), Klee_2021, Jackson_2023). However, due to the prevalence of this variant in controls, these report(s) do not provide unequivocal conclusions about association of the variant with Ectodermal Dysplasia 14, Hair/tooth Type With Or Without Hypohidrosis. In at least 1 family, this variant was found to segregate with disease in 2 affected siblings (Labcorp Genetics, (formerly Invitae)). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34042254, 27736875, 28409725, 33144682, 37853563, 30046887, 37009414, 29144512). ClinVar contains an entry for this variant (Variation ID: 227135). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

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]. -

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	T
BayesDel_noAF	Benign	-0.46
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.4	M;M
PhyloP100		7.1
PrimateAI	Uncertain	0.64	T
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	T
GERP RS		4.3
Varity_R		0.42
gMVP		0.66
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs138480801; hg19: chr21-45919761; COSMIC: COSV107388839; COSMIC: COSV107388839;