chr21-44533890-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_144991.3(TSPEAR):c.337G>A(p.Glu113Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,611,910 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0025 ( 9 hom. )

Consequence

TSPEAR
NM_144991.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.03

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 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

TSPEAR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037771463).

BP6

Variant 21-44533890-C-T is Benign according to our data. Variant chr21-44533890-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228052.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPEAR	NM_144991.3 link	c.337G>A	p.Glu113Lys	missense_variant	Exon 3 of 12	ENST00000323084.9	NP_659428.2	Q8WU66-1
TSPEAR	NM_001272037.2 link	c.133G>A	p.Glu45Lys	missense_variant	Exon 4 of 13		NP_001258966.1	Q8WU66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TSPEAR	ENST00000323084.9 link	c.337G>A	p.Glu113Lys	missense_variant	Exon 3 of 12	1	NM_144991.3	ENSP00000321987.4	Q8WU66-1
TSPEAR	ENST00000397916.1 link	n.292G>A		non_coding_transcript_exon_variant	Exon 3 of 11	1
TSPEAR	ENST00000642437.1 link	n.*282G>A		non_coding_transcript_exon_variant	Exon 4 of 13			ENSP00000496535.1	A0A2R8YFK6
TSPEAR	ENST00000642437.1 link	n.*282G>A		3_prime_UTR_variant	Exon 4 of 13			ENSP00000496535.1	A0A2R8YFK6

Frequencies

GnomAD3 genomes

AF:

0.00194

AC:

294

AN:

151620

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000509

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00296

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00175

AC:

430

AN:

246242

AF XY:

0.00180

show subpopulations

Gnomad AFR exome

AF:

0.000442

Gnomad AMR exome

AF:

0.00186

Gnomad ASJ exome

AF:

0.00151

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000746

Gnomad NFE exome

AF:

0.00293

Gnomad OTH exome

AF:

0.000996

GnomAD4 exome

AF:

0.00249

AC:

3629

AN:

1460172

Hom.:

Cov.:

AF XY:

0.00249

AC XY:

1806

AN XY:

726362

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33474

American (AMR)

AF:

0.00199

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00134

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.000826

AC:

AN:

52042

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00297

AC:

3305

AN:

1111794

Other (OTH)

AF:

0.00225

AC:

136

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

186

372

559

745

931

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

122

244

366

488

610

<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:

0.00194

AC:

294

AN:

151738

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

139

AN XY:

74116

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

41350

American (AMR)

AF:

0.00308

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5040

South Asian (SAS)

AF:

0.00

AC:

AN:

4786

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00296

AC:

201

AN:

67924

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00254

Hom.:

Bravo

AF:

0.00235

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000456

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00164

AC:

198

EpiCase

AF:

0.00376

EpiControl

AF:

0.00350

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TSPEAR: BS2 -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Inborn genetic diseases

Uncertain:1

Jun 29, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.337G>A (p.E113K) alteration is located in exon 3 (coding exon 3) of the TSPEAR gene. This alteration results from a G to A substitution at nucleotide position 337, causing the glutamic acid (E) at amino acid position 113 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

TSPEAR-related disorder

Benign:1

Apr 25, 2024

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). -

not specified

Benign:1

Aug 10, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Glu113Lys in exon 3 of TSPEAR: This variant is not expected to have clinical significance because it has been identified in 0.3% (331/123288) of European chr omosomes including 1 homozygote by the Genome Aggregation Database (gnomAD, http ://gnomad.broadinstitute.org; dbSNP rs144166142). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.066

T;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.75

.;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.5

L;L

PhyloP100

2.0

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.2

.;N

REVEL

Benign

0.092

Sift

Benign

0.30

.;T

Sift4G

Benign

0.30

T;T

Polyphen

0.0080

B;B

Vest4

0.23

MVP

0.085

MPC

0.055

ClinPred

0.0042

GERP RS

2.9

Varity_R

0.095

gMVP

0.42

Mutation Taster

=92/8

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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