21-44509225-GAC-AA

Position:

• chr21-44509225-GAC-AA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_144991.3(TSPEAR):​c.1726_1728delGTCinsTT​(p.Val576fs) variant causes a frameshift, synonymous change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. VK576L?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSPEAR NM_144991.3 frameshift, synonymous
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.33

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-AS1 (HGNC:1271): (TSPEAR antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 18 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 21-44509225-GAC-AA is Pathogenic according to our data. Variant chr21-44509225-GAC-AA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 584443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPEAR	NM_144991.3	c.1726_1728delGTCinsTT	p.Val576fs	frameshift_variant, synonymous_variant	10/12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.1522_1524delGTCinsTT	p.Val508fs	frameshift_variant, synonymous_variant	11/13		NP_001258966.1
TSPEAR-AS1	NR_103707.1	n.1215-27_1215-25delGACinsAA		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9	c.1726_1728delGTCinsTT	p.Val576fs	frameshift_variant, synonymous_variant	10/12	1	NM_144991.3	ENSP00000321987.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2024	Reported in the homozygous state and with a second variant in the TSPEAR gene in several unrelated patients with dental anomalies, scalp hypotrichosis, and dysmorphic facial features in the literature (PMID: 30046887, 34042254, 27736875); Published functional studies suggest a damaging effect by altering the protein localization and secretion (PMID: 22678063); Frameshift variant predicted to result in protein truncation, as the last 94 amino acids are replaced with 37 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22678063, 34042254, 27736875, 30046887) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 09, 2024	This sequence change creates a premature translational stop signal (p.Val576Leufs*38) in the TSPEAR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 94 amino acid(s) of the TSPEAR protein. This variant is present in population databases (rs782540538, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with ectodermal dysplasia and/or tooth agenesis (PMID: 27736875, 30046887). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1726G>T + c.1728del. ClinVar contains an entry for this variant (Variation ID: 37311). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

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

- -

Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 23, 2020

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1569151872; hg19: chr21-45929108;