21-44504784-A-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_144991.3(TSPEAR):c.1852T>A(p.Tyr618Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TSPEAR
NM_144991.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 8.25

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPEAR	NM_144991.3 link	c.1852T>A	p.Tyr618Asn	missense_variant	Exon 11 of 12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2 link	c.1648T>A	p.Tyr550Asn	missense_variant	Exon 12 of 13		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TSPEAR	ENST00000323084.9 link	c.1852T>A	p.Tyr618Asn	missense_variant	Exon 11 of 12	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1 link	n.*1797T>A		non_coding_transcript_exon_variant	Exon 12 of 13			ENSP00000496535.1
TSPEAR	ENST00000642437.1 link	n.*1797T>A		3_prime_UTR_variant	Exon 12 of 13			ENSP00000496535.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251280

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460728

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726760

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33440

American (AMR)

AF:

0.0000224

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53304

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111110

Other (OTH)

AF:

0.00

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Pathogenic:1

Dec 05, 2022

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

not specified

Uncertain:1

Jan 31, 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.1852T>A (p.Tyr618Asn) results in a non-conservative amino acid change located in the EAR repeat domain (IPR009039) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251280 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1852T>A has been reported in the literature in one individual affected with Ectodermal Dysplasia and the 2ed variant appeared to be likely benign (Peled_2016) . These report(s) do not provide unequivocal conclusions about association of the variant with Ectodermal Dysplasia 14, Hair/tooth Type With Or Without Hypohidrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 27736875). ClinVar contains an entry for this variant (Variation ID: 590273). Based on the evidence outlined above, the variant was classified as uncertain significance.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

D;D

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.0

.;D

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Uncertain

0.79

MutationAssessor

Pathogenic

3.3

M;M

PhyloP100

8.3

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.0

.;D

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

.;D

Vest4

0.0

ClinPred

0.97

GERP RS

4.7

Varity_R

0.86

gMVP

0.81

Mutation Taster

=15/85

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over