21-44529886-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_144991.3(TSPEAR):c.702C>T(p.Asn234Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00567 in 1,613,222 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0058 ( 27 hom. )

Consequence

TSPEAR
NM_144991.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.06

Publications

3 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:

LOC124905038 (HGNC:):

LOC124905038 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 21-44529886-G-A is Benign according to our data. Variant chr21-44529886-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.07 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0045 (686/152340) while in subpopulation NFE AF = 0.00817 (556/68022). AF 95% confidence interval is 0.00761. There are 5 homozygotes in GnomAd4. There are 348 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPEAR	NM_144991.3 link	c.702C>T	p.Asn234Asn	synonymous_variant	Exon 5 of 12	ENST00000323084.9	NP_659428.2	Q8WU66-1
TSPEAR	NM_001272037.2 link	c.498C>T	p.Asn166Asn	synonymous_variant	Exon 6 of 13		NP_001258966.1	Q8WU66
LOC124905038	XR_007067905.1 link	n.2378G>A		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TSPEAR	ENST00000323084.9 link	c.702C>T	p.Asn234Asn	synonymous_variant	Exon 5 of 12	1	NM_144991.3	ENSP00000321987.4	Q8WU66-1
TSPEAR	ENST00000397916.1 link	n.657C>T		non_coding_transcript_exon_variant	Exon 5 of 11	1
TSPEAR	ENST00000642437.1 link	n.*647C>T		non_coding_transcript_exon_variant	Exon 6 of 13			ENSP00000496535.1	A0A2R8YFK6
TSPEAR	ENST00000642437.1 link	n.*647C>T		3_prime_UTR_variant	Exon 6 of 13			ENSP00000496535.1	A0A2R8YFK6

Frequencies

GnomAD3 genomes

AF:

0.00450

AC:

685

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00817

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00445

AC:

1113

AN:

249956

AF XY:

0.00433

show subpopulations

Gnomad AFR exome

AF:

0.00130

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00242

Gnomad NFE exome

AF:

0.00842

Gnomad OTH exome

AF:

0.00410

GnomAD4 exome

AF:

0.00579

AC:

8456

AN:

1460882

Hom.:

Cov.:

AF XY:

0.00550

AC XY:

3999

AN XY:

726792

show subpopulations

African (AFR)

AF:

0.000896

AC:

AN:

33468

American (AMR)

AF:

0.00130

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26102

East Asian (EAS)

AF:

0.000101

AC:

AN:

39696

South Asian (SAS)

AF:

0.000197

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00306

AC:

161

AN:

52700

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00713

AC:

7930

AN:

1111840

Other (OTH)

AF:

0.00421

AC:

254

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

469

938

1407

1876

2345

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

276

552

828

1104

1380

<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:

0.00450

AC:

686

AN:

152340

Hom.:

Cov.:

AF XY:

0.00467

AC XY:

348

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41574

American (AMR)

AF:

0.00340

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00198

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00817

AC:

556

AN:

68022

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

126

158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00676

Hom.:

Bravo

AF:

0.00409

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00660

EpiControl

AF:

0.00623

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 24, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

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: BP4, BP7, BS2 -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TSPEAR-related disorder

Benign:1

Mar 09, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

not specified

Benign:1

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Asn234Asn in exon 5 of TSPEAR: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 0.6% (51/8600) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs117791519). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.8

(source)

DANN

Benign

0.91

PhyloP100

-1.1

Mutation Taster

=100/0

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

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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