NM_144991.3:c.364C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_144991.3(TSPEAR):c.364C>T(p.Arg122Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,612,382 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R122Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000062 ( 1 hom. )

Consequence

TSPEAR
NM_144991.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.604

Publications

4 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_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23562929).

BP6

Variant 21-44533863-G-A is Benign according to our data. Variant chr21-44533863-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 229377.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPEAR	NM_144991.3 link	c.364C>T	p.Arg122Trp	missense_variant	Exon 3 of 12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2 link	c.160C>T	p.Arg54Trp	missense_variant	Exon 4 of 13		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TSPEAR	ENST00000323084.9 link	c.364C>T	p.Arg122Trp	missense_variant	Exon 3 of 12	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000397916.1 link	n.319C>T		non_coding_transcript_exon_variant	Exon 3 of 11	1
TSPEAR	ENST00000642437.1 link	n.*309C>T		non_coding_transcript_exon_variant	Exon 4 of 13			ENSP00000496535.1
TSPEAR	ENST00000642437.1 link	n.*309C>T		3_prime_UTR_variant	Exon 4 of 13			ENSP00000496535.1

Frequencies

GnomAD3 genomes

AF:

0.000625

AC:

AN:

151930

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00220

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000150

AC:

AN:

247062

AF XY:

0.000119

show subpopulations

Gnomad AFR exome

AF:

0.00152

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000110

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000272

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1460334

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

726458

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

33476

American (AMR)

AF:

0.000112

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.000151

AC:

AN:

39692

South Asian (SAS)

AF:

0.000128

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1111886

Other (OTH)

AF:

0.0000828

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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

AF:

0.000625

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.000485

AC XY:

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.00219

AC:

AN:

41498

American (AMR)

AF:

0.000131

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5072

South Asian (SAS)

AF:

0.000208

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67986

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

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:

0.000343

Hom.:

Bravo

AF:

0.000725

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000166

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Aug 26, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 122 of the TSPEAR protein (p.Arg122Trp). This variant is present in population databases (rs146257403, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with TSPEAR-related conditions. ClinVar contains an entry for this variant (Variation ID: 229377). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSPEAR protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

May 27, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Arg122Trp var iant in TSPEAR has not been previously reported in individuals with hearing loss . This variant has been identified in 0.15% (14/9534) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 146257403). Computational prediction tools and conservation analyses do not pro vide strong support for or against an impact to the protein In summary, while th e clinical significance of the p.Arg122Trp variant is uncertain, the frequency d ata suggests that it is more likely to be benign. -

Autosomal recessive nonsyndromic hearing loss 98

Uncertain:1

Jul 08, 2019

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;T

Eigen

Benign

0.11

Eigen_PC

Benign

-0.074

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.94

.;D

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-0.45

MutationAssessor

Pathogenic

3.0

M;M

PhyloP100

0.60

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-4.1

.;D

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.010

D;D

Polyphen

1.0

D;D

Vest4

0.59

MVP

0.22

MPC

0.34

ClinPred

0.46

GERP RS

3.0

Varity_R

0.52

gMVP

0.85

Mutation Taster

=66/34

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