rs117034581

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• PP3: Splicing predictors support a deleterious 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 VariationId is 504869.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.1566+5G>A		splice_region intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.1362+5G>A		splice_region intron	N/A	NP_001258966.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.1566+5G>A		splice_region intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000397916.1	TSL:1	n.1521+5G>A		splice_region intron	N/A
	TSPEAR	ENST00000943283.1		c.1566+5G>A		splice_region intron	N/A	ENSP00000613342.1

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

GnomAD2 exomes AF: 0.00109 AC: 274 AN: 250250 AF XY: 0.00102

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 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

African (AFR) AF: 0.000478 AC: 16 AN: 33468

American (AMR) AF: 0.000313 AC: 14 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.000114 AC: 6 AN: 52820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00247 AC: 2746 AN: 1111524

Other (OTH) AF: 0.00103 AC: 62 AN: 60362

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

African (AFR) AF: 0.000409 AC: 17 AN: 41554

American (AMR) AF: 0.000392 AC: 6 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00271 AC: 184 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00219 Hom.: 0

Bravo AF: 0.00134

EpiCase AF: 0.00240

EpiControl AF: 0.00190

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	not specified (1)
-	-	1	TSPEAR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Benign	0.97
PhyloP100		6.9
Mutation Taster		=35/65	disease causing

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

Other links and lift over

dbSNP: rs117034581; hg19: chr21-45941761;