rs147258456

Positions:

• chr21-44509207-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_144991.3(TSPEAR):​c.1746C>T​(p.Leu582=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,613,766 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (12 hom.)
• Consequence: TSPEAR NM_144991.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.05

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 21-44509207-G-A is Benign according to our data. Variant chr21-44509207-G-A is described in ClinVar as [Benign]. Clinvar id is 504823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44509207-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.05 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPEAR	NM_144991.3	c.1746C>T	p.Leu582=	synonymous_variant	10/12	ENST00000323084.9	NP_659428.2
TSPEAR-AS1	NR_103707.1	n.1215-45G>A		intron_variant, non_coding_transcript_variant
TSPEAR	NM_001272037.2	c.1542C>T	p.Leu514=	synonymous_variant	11/13		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9	c.1746C>T	p.Leu582=	synonymous_variant	10/12	1	NM_144991.3	ENSP00000321987	P1
TSPEAR	ENST00000397916.1	n.1701C>T		non_coding_transcript_exon_variant	10/11	1
TSPEAR-AS1	ENST00000451035.2	n.770-45G>A		intron_variant, non_coding_transcript_variant		5
TSPEAR	ENST00000642437.1	c.*1691C>T		3_prime_UTR_variant, NMD_transcript_variant	11/13			ENSP00000496535

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 361 AN: 152164 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00325 AC: 816 AN: 250994 Hom.: 4 AF XY: 0.00314 AC XY: 426 AN XY: 135724

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0151

Gnomad NFE exome AF: 0.00394

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00234 AC: 3420 AN: 1461484 Hom.: 12 Cov.: 32 AF XY: 0.00224 AC XY: 1629 AN XY: 727002

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0145

Gnomad4 NFE exome AF: 0.00222

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.00237 AC: 361 AN: 152282 Hom.: 4 Cov.: 32 AF XY: 0.00295 AC XY: 220 AN XY: 74462

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0166

Gnomad4 NFE AF: 0.00228

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00188 Hom.: 0

Bravo AF: 0.00133

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00207

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Leu582Leu in exon 10 of TSPEAR: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.3% (26/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs147258456). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.3
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs147258456; hg19: chr21-45929090;