rs117034581

chr21-44521878-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3 BP6

The NM_144991.3(TSPEAR):c.1566+5G>A variant causes a splice donor 5th base, 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. 2/2 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_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9988
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• 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:16428): (TSPEAR antisense RNA 2)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. 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: {Uncertain_significance=1, Likely_benign=3}. Variant chr21-44521878-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPEAR	NM_144991.3	c.1566+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000323084.9
TSPEAR	NM_001272037.2	c.1362+5G>A		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPEAR	ENST00000323084.9	c.1566+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_144991.3	P1
TSPEAR	ENST00000397916.1	n.1521+5G>A		splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant		1
TSPEAR-AS2	ENST00000465978.1	n.217-3946C>T		intron_variant, non_coding_transcript_variant		5
TSPEAR	ENST00000642437.1	c.*1511+5G>A		splice_donor_5th_base_variant, intron_variant, NMD_transcript_variant

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:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	TSPEAR: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 02, 2016

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. -

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;