rs117034581

Variant names:

• chr21-44521878-C-T
• rs117034581
• NM_144991.3:c.1566+5G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3 BP6 BS2

The NM_144991.3(TSPEAR):​c.1566+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0019 in 1,612,918 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (4 hom.)
• Consequence: TSPEAR NM_144991.3 splice_region, intron
• Scores: Splicing: ADA: 0.9988
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 6.94

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-AS2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BP6: Variant 21-44521878-C-T is Benign according to our data. Variant chr21-44521878-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504869.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr21-44521878-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPEAR	NM_144991.3	c.1566+5G>A		splice_region_variant, intron_variant	Intron 9 of 11	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.1362+5G>A		splice_region_variant, intron_variant	Intron 10 of 12		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9	c.1566+5G>A		splice_region_variant, intron_variant	Intron 9 of 11	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000397916.1	n.1521+5G>A		splice_region_variant, intron_variant	Intron 9 of 10	1
TSPEAR-AS2	ENST00000465978.1	n.217-3946C>T		intron_variant	Intron 1 of 1	5
TSPEAR	ENST00000642437.1	n.*1511+5G>A		splice_region_variant, intron_variant	Intron 10 of 12			ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 209 AN: 152106 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00271

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00109 AC: 274 AN: 250250 Hom.: 0 AF XY: 0.00102 AC XY: 138 AN XY: 135366

Gnomad AFR exome AF: 0.000681

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00220

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.00195 AC: 2849 AN: 1460694 Hom.: 4 Cov.: 32 AF XY: 0.00189 AC XY: 1374 AN XY: 726546

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000114

Gnomad4 NFE exome AF: 0.00247

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.00137 AC: 209 AN: 152224 Hom.: 1 Cov.: 33 AF XY: 0.00121 AC XY: 90 AN XY: 74424

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00271

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00219 Hom.: 0

Bravo AF: 0.00134

EpiCase AF: 0.00240

EpiControl AF: 0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Jan 27, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TSPEAR: BS2 -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

May 02, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The c.1566+5G>A var iant in TSPEAR has not been previously reported in individuals with hearing loss , but has been identified in 0.2% (112/65824) of European chromosomes by the Exo me Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1170345 81). This variant is located in the 5' splice region. Computational tools do not suggest an impact to splicing. However, this information is not predictive enou gh to rule out pathogenicity. In summary, while the clinical significance of the c.1566+5G>A variant is uncertain, its frequency suggests that it is more likely to be benign. -

TSPEAR-related disorder Benign:1

Sep 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Benign	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.33		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs117034581; hg19: chr21-45941761;