NM_144991.3:c.343G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_144991.3(TSPEAR):c.343G>A(p.Asp115Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000974 in 1,611,820 control chromosomes in the GnomAD database, including 11 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). Synonymous variant affecting the same amino acid position (i.e. D115D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 29)

Exomes 𝑓: 0.00088 ( 9 hom. )

Consequence

TSPEAR
NM_144991.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.775

Publications

1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive nonsyndromic hearing loss 98
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003951758).

BP6

Variant 21-44533884-C-T is Benign according to our data. Variant chr21-44533884-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 504830.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00186 (282/151556) while in subpopulation AFR AF = 0.00441 (182/41298). AF 95% confidence interval is 0.00388. There are 2 homozygotes in GnomAd4. There are 142 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144991.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPEAR	NM_144991.3	MANE Select	c.343G>A	p.Asp115Asn	missense	Exon 3 of 12	NP_659428.2
	TSPEAR	NM_001272037.2		c.139G>A	p.Asp47Asn	missense	Exon 4 of 13	NP_001258966.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.343G>A	p.Asp115Asn	missense	Exon 3 of 12	ENSP00000321987.4	Q8WU66-1
TSPEAR	ENST00000397916.1	TSL:1	n.298G>A		non_coding_transcript_exon	Exon 3 of 11
TSPEAR	ENST00000943283.1		c.343G>A	p.Asp115Asn	missense	Exon 3 of 13	ENSP00000613342.1

Frequencies

GnomAD3 genomes

AF:

0.00182

AC:

275

AN:

151440

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00425

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00158

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000629

Gnomad FIN

AF:

0.0000947

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000766

Gnomad OTH

AF:

0.00530

GnomAD2 exomes

AF:

0.00118

AC:

290

AN:

246454

AF XY:

0.00118

show subpopulations

Gnomad AFR exome

AF:

0.00405

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.000403

Gnomad EAS exome

AF:

0.0000547

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00108

Gnomad OTH exome

AF:

0.00298

GnomAD4 exome

AF:

0.000882

AC:

1288

AN:

1460264

Hom.:

Cov.:

AF XY:

0.000887

AC XY:

644

AN XY:

726438

show subpopulations

African (AFR)

AF:

0.00544

AC:

182

AN:

33476

American (AMR)

AF:

0.00127

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.000613

AC:

AN:

26120

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.00152

AC:

131

AN:

86250

European-Finnish (FIN)

AF:

0.0000384

AC:

AN:

52048

Middle Eastern (MID)

AF:

0.0236

AC:

136

AN:

5768

European-Non Finnish (NFE)

AF:

0.000571

AC:

635

AN:

1111842

Other (OTH)

AF:

0.00212

AC:

128

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

157

235

314

392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00186

AC:

282

AN:

151556

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

142

AN XY:

73990

show subpopulations

African (AFR)

AF:

0.00441

AC:

182

AN:

41298

American (AMR)

AF:

0.00157

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5026

South Asian (SAS)

AF:

0.000629

AC:

AN:

4766

European-Finnish (FIN)

AF:

0.0000947

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000766

AC:

AN:

67886

Other (OTH)

AF:

0.00524

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

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:

0.00112

Hom.:

Bravo

AF:

0.00210

ESP6500AA

AF:

0.00456

AC:

ESP6500EA

AF:

0.000931

AC:

ExAC

AF:

0.00115

AC:

139

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00190

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (1)

TSPEAR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.038

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.015

MetaRNN

Benign

0.0040

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.6

PhyloP100

0.78

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.45

REVEL

Benign

0.045

Sift

Benign

0.46

Sift4G

Benign

0.53

Polyphen

0.010

Vest4

0.21

MVP

0.014

MPC

0.063

ClinPred

0.0017

GERP RS

3.1

Varity_R

0.032

gMVP

0.44

Mutation Taster

=91/9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over