21-44499787-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_144991.3(TSPEAR):c.2006G>A(p.Arg669His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000965 in 1,565,322 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R669C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000091 ( 0 hom. )

Consequence

TSPEAR
NM_144991.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.150

Publications

0 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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03151557).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPEAR	NM_144991.3 link	c.2006G>A	p.Arg669His	missense_variant	Exon 12 of 12	ENST00000323084.9	NP_659428.2	Q8WU66-1
TSPEAR	NM_001272037.2 link	c.1802G>A	p.Arg601His	missense_variant	Exon 13 of 13		NP_001258966.1	Q8WU66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TSPEAR	ENST00000323084.9 link	c.2006G>A	p.Arg669His	missense_variant	Exon 12 of 12	1	NM_144991.3	ENSP00000321987.4	Q8WU66-1
TSPEAR	ENST00000642437.1 link	n.*1951G>A		non_coding_transcript_exon_variant	Exon 13 of 13			ENSP00000496535.1	A0A2R8YFK6
TSPEAR	ENST00000642437.1 link	n.*1951G>A		3_prime_UTR_variant	Exon 13 of 13			ENSP00000496535.1	A0A2R8YFK6

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000121

AC:

AN:

174004

AF XY:

0.0000853

show subpopulations

Gnomad AFR exome

AF:

0.000524

Gnomad AMR exome

AF:

0.0000731

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000169

Gnomad OTH exome

AF:

0.000215

GnomAD4 exome

AF:

0.0000906

AC:

128

AN:

1413126

Hom.:

Cov.:

AF XY:

0.0000959

AC XY:

AN XY:

698838

show subpopulations

African (AFR)

AF:

0.000345

AC:

AN:

31930

American (AMR)

AF:

0.0000521

AC:

AN:

38378

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25164

East Asian (EAS)

AF:

0.00

AC:

AN:

36642

South Asian (SAS)

AF:

0.0000124

AC:

AN:

80414

European-Finnish (FIN)

AF:

0.0000409

AC:

AN:

48878

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4684

European-Non Finnish (NFE)

AF:

0.0000983

AC:

107

AN:

1088586

Other (OTH)

AF:

0.0000855

AC:

AN:

58450

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000151

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.000290

AC:

AN:

41440

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00115

Hom.:

Bravo

AF:

0.000170

ExAC

AF:

0.0000591

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Dec 21, 2023

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 histidine, which is basic and polar, at codon 669 of the TSPEAR protein (p.Arg669His). This variant is present in population databases (rs184873531, gnomAD 0.02%). 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: 1313657). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Oct 19, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases

Uncertain:1

Apr 25, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2006G>A (p.R669H) alteration is located in exon 12 (coding exon 12) of the TSPEAR gene. This alteration results from a G to A substitution at nucleotide position 2006, causing the arginine (R) at amino acid position 669 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.67

CADD

Benign

4.2

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.018

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.69

.;T

M_CAP

Benign

0.0070

MetaRNN

Benign

0.032

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

N;N

PhyloP100

-0.15

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.10

.;N

REVEL

Benign

0.023

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

.;D

Polyphen

0.0

B;B

Vest4

0.13

MVP

0.014

MPC

0.30

ClinPred

0.080

GERP RS

-3.6

Varity_R

0.059

gMVP

0.30

Mutation Taster

=98/2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

21-44499787-C-T

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