21-44531087-G-A

Position:

chr21-44531087-G-A

Variant summary

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

The NM_144991.3(TSPEAR):c.589C>T(p.Arg197*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000565 in 1,613,608 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00060 ( 1 hom. )

Consequence

TSPEAR
NM_144991.3 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: 0.747

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:

TSPEAR (HGNC:):

TSPEAR 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 21-44531087-G-A is Pathogenic according to our data. Variant chr21-44531087-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 403572.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=5, Likely_pathogenic=1}. Variant chr21-44531087-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPEAR	NM_144991.3 linkuse as main transcript	c.589C>T	p.Arg197*	stop_gained	4/12	ENST00000323084.9	NP_659428.2	Q8WU66-1
TSPEAR	NM_001272037.2 linkuse as main transcript	c.385C>T	p.Arg129*	stop_gained	5/13		NP_001258966.1	Q8WU66
LOC124905038	XR_007067905.1 linkuse as main transcript	n.3579G>A		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9 linkuse as main transcript	c.589C>T	p.Arg197*	stop_gained	4/12	1	NM_144991.3	ENSP00000321987.4		Q8WU66-1

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000319

AC:

AN:

250544

Hom.:

AF XY:

0.000339

AC XY:

AN XY:

135702

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000646

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000597

AC:

873

AN:

1461474

Hom.:

Cov.:

AF XY:

0.000558

AC XY:

406

AN XY:

727012

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000207

Gnomad4 NFE exome

AF:

0.000748

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.000256

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000392

Hom.:

Bravo

AF:

0.000253

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000321

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2024	Observed multiple times with another TSPEAR variant in unrelated patients in published literature with ectodermal dysplasia or oligodontia, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 34042254, 37009414); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27736875, 33144682, 37009414, 34042254) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2023	This sequence change creates a premature translational stop signal (p.Arg197) 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 (rs139455627, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with clinical features of ectodermal dysplasia (PMID: 34042254; Invitae). This variant is also known as c.385C>T, p.Arg129. ClinVar contains an entry for this variant (Variation ID: 403572). For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 21, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Aug 03, 2022	This sequence variant is a single nucleotide substitution (C>T) at coding nucleotide 589 in the TSPEAR gene which changes the arginine 197 codon into an early termition sigl. As it occurs in exon 4 of 12, this variant is predicted to generate a non-functiol allele through the expression of a truncated protein or a loss of TSPEAR expression due to nonsense-mediated decay. This is a previously reported variant (ClinVar) which has been observed with a second variant in multiple individuals with ectodermal dysplasia with and without tooth agenesis (PMID: 34042254). This variant is present in 86 of 281928 alleles (0.03%) in the gnomAD control population dataset. Given the data, we consider this variant to be pathogenic. ACMG Criteria: PM3, PP4, PVS1 -

TSPEAR-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 2024

The TSPEAR c.589C>T variant is predicted to result in premature protein termination (p.Arg197*). This variant, also reported as c.385C>T (p.Arg129*) using a different transcript (NM_001272037.1), has been reported in the homozygous and compound heterozygous states in individuals with TSPEAR-related disorders (Klee et al. 2021. PubMed ID: 33144682; Bowles et al. 2021. PubMed ID: 34042254; Jackson et al. 2023. PubMed ID: 37009414). This variant is reported in 0.059% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in TSPEAR are expected to be pathogenic. This variant is interpreted as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2019

- -

TSPEAR-related disorder of tooth and hair follicle morphogenesis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Jun 25, 2018

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 25, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: One frameshift variant in the gene has been reported in a consanguineous family with AR deafness (Delmaghani 2012). Variant segregated in 2 affected siblings. Variant disrupts protein function when transfected into cells in vitro. Limited evidence for gene's association with disease. Does not meet criteria for reporting in BabySeq. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.71

Vest4

0.13

GERP RS

2.4

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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