21-44529874-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_144991.3(TSPEAR):c.714G>A(p.Ala238Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,613,622 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00088 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 7 hom. )

Consequence

TSPEAR
NM_144991.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -4.96

Publications

2 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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 21-44529874-C-T is Benign according to our data. Variant chr21-44529874-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 228055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.95 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TSPEAR	NM_144991.3 link	c.714G>A	p.Ala238Ala	synonymous_variant	Exon 5 of 12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2 link	c.510G>A	p.Ala170Ala	synonymous_variant	Exon 6 of 13		NP_001258966.1
LOC124905038	XR_007067905.1 link	n.2366C>T		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TSPEAR	ENST00000323084.9 link	c.714G>A	p.Ala238Ala	synonymous_variant	Exon 5 of 12	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000397916.1 link	n.669G>A		non_coding_transcript_exon_variant	Exon 5 of 11	1
TSPEAR	ENST00000642437.1 link	n.*659G>A		non_coding_transcript_exon_variant	Exon 6 of 13			ENSP00000496535.1
TSPEAR	ENST00000642437.1 link	n.*659G>A		3_prime_UTR_variant	Exon 6 of 13			ENSP00000496535.1

Frequencies

GnomAD3 genomes

AF:

0.000874

AC:

133

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000985

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00102

AC:

256

AN:

250496

AF XY:

0.000966

show subpopulations

Gnomad AFR exome

AF:

0.000494

Gnomad AMR exome

AF:

0.000550

Gnomad ASJ exome

AF:

0.0108

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000327

Gnomad NFE exome

AF:

0.000883

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.00125

AC:

1829

AN:

1461310

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

874

AN XY:

726978

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33474

American (AMR)

AF:

0.000515

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

295

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000566

AC:

AN:

53038

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00124

AC:

1377

AN:

1111902

Other (OTH)

AF:

0.00147

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

108

216

325

433

541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.000880

AC:

134

AN:

152312

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41572

American (AMR)

AF:

0.000523

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000985

AC:

AN:

68006

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.00184

Hom.:

Bravo

AF:

0.000899

EpiCase

AF:

0.000927

EpiControl

AF:

0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TSPEAR: BP4, BP7 -

Oct 28, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

May 16, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ala238Ala in exon 5 of TSPEAR: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 1.1% (113/10126) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http:/ /gnomad.broadinstitute.org/; dbSNP rs146025689). -

TSPEAR-related disorder

Benign:1

May 14, 2022

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.29

(source)

DANN

Benign

0.92

PhyloP100

-5.0

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