chr21-44509225-GAC-AA

Variant names:

• chr21-44509225-GAC-AA
• rs1569151872
• NM_144991.3:c.1726_1728delGTCinsTT

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_144991.3(TSPEAR):​c.1726_1728delGTCinsTT​(p.Val576LeufsTer38) 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 (★★). ClinVar reports functional evidence for this variant: "SCV003933339: Published functional studies suggest a damaging effect by altering the protein localization and secretion (PMID:22678063)". 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
• Publications: 0 publications found

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

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV003933339: Published functional studies suggest a damaging effect by altering the protein localization and secretion (PMID: 22678063)
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 584443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144991.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPEAR	NM_144991.3	MANE Select	c.1726_1728delGTCinsTT	p.Val576LeufsTer38	frameshift synonymous	Exon 10 of 12	NP_659428.2
	TSPEAR	NM_001272037.2		c.1522_1524delGTCinsTT	p.Val508LeufsTer38	frameshift synonymous	Exon 11 of 13	NP_001258966.1
	TSPEAR-AS1	NR_103707.1		n.1215-27_1215-25delGACinsAA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.1726_1728delGTCinsTT	p.Val576LeufsTer38	frameshift synonymous	Exon 10 of 12	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000397916.1	TSL:1	n.1681_1683delGTCinsTT		non_coding_transcript_exon	Exon 10 of 11
	TSPEAR	ENST00000943283.1		c.1726_1728delGTCinsTT	p.Val576LeufsTer45	frameshift synonymous	Exon 10 of 13	ENSP00000613342.1

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis (1)
1	-	-	TSPEAR-related disorder of tooth and hair follicle morphogenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.3
Mutation Taster		=4/196	disease causing

Splicing

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

Other links and lift over

dbSNP: rs1569151872; hg19: chr21-45929108;