rs782471965

Positions:

chr21-44528572-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The ENST00000323084.9(TSPEAR):c.802C>T(p.Arg268Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,792 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 Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

TSPEAR
ENST00000323084.9 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 1.59

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 links:

LOC124905038 (HGNC:):

LOC124905038 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 21-44528572-G-A is Pathogenic according to our data. Variant chr21-44528572-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505557.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TSPEAR	NM_144991.3 linkuse as main transcript	c.802C>T	p.Arg268Ter	stop_gained	6/12	ENST00000323084.9	NP_659428.2
LOC124905038	XR_007067905.1 linkuse as main transcript	n.1064G>A		non_coding_transcript_exon_variant	1/2
TSPEAR	NM_001272037.2 linkuse as main transcript	c.598C>T	p.Arg200Ter	stop_gained	7/13		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9 linkuse as main transcript	c.802C>T	p.Arg268Ter	stop_gained	6/12	1	NM_144991.3	ENSP00000321987	P1	Q8WU66-1
TSPEAR	ENST00000397916.1 linkuse as main transcript	n.757C>T		non_coding_transcript_exon_variant	6/11	1
TSPEAR	ENST00000642437.1 linkuse as main transcript	c.*747C>T		3_prime_UTR_variant, NMD_transcript_variant	7/13			ENSP00000496535

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

250964

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135692

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1461546

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727072

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2023

ClinVar contains an entry for this variant (Variation ID: 505557). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with TSPEAR-related conditions. This sequence change creates a premature translational stop signal (p.Arg268*) in the TSPEAR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSPEAR are known to be pathogenic (PMID: 34042254). This variant is present in population databases (rs782471965, gnomAD 0.0009%). -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 17, 2017

The p.Arg268X variant in TSPEAR has not been previously reported in individuals with hearing loss, but has been identified in 1/66396 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s782471965). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This nonsense varian t leads to a premature termination codon at position 268, which is predicted to lead to a truncated or absent protein. However, there is only moderate evidence to support an association of TSPEAR with autosomal recessive nonsyndromic hearin g loss. In summary, the clinical significance of the p.Arg268X variant is uncert ain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.21

Eigen_PC

Benign

-0.053

FATHMM_MKL

Benign

0.70

MutationTaster

Benign

1.0

A;A

Vest4

0.28

GERP RS

2.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over