rs115847549

Variant names:

• chr21-44509309-G-A
• rs115847549
• NM_144991.3:c.1644C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_144991.3(TSPEAR):​c.1644C>T​(p.Tyr548Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,613,960 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (30 hom.)
• Consequence: TSPEAR NM_144991.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.986
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 21-44509309-G-A is Benign according to our data. Variant chr21-44509309-G-A is described in ClinVar as Benign. ClinVar VariationId is 227131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.986 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0103 (1563/152174) while in subpopulation AFR AF = 0.0325 (1347/41474). AF 95% confidence interval is 0.031. There are 28 homozygotes in GnomAd4. There are 739 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 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.1644C>T	p.Tyr548Tyr	synonymous	Exon 10 of 12	NP_659428.2
	TSPEAR	NM_001272037.2		c.1440C>T	p.Tyr480Tyr	synonymous	Exon 11 of 13	NP_001258966.1
	TSPEAR-AS1	NR_103707.1		n.1272G>A		non_coding_transcript_exon	Exon 5 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.1644C>T	p.Tyr548Tyr	synonymous	Exon 10 of 12	ENSP00000321987.4
	TSPEAR	ENST00000397916.1	TSL:1	n.1599C>T		non_coding_transcript_exon	Exon 10 of 11
	TSPEAR	ENST00000943283.1		c.1644C>T	p.Tyr548Tyr	synonymous	Exon 10 of 13	ENSP00000613342.1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1559 AN: 152056 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00394 AC: 991 AN: 251282 AF XY: 0.00342

Gnomad AFR exome AF: 0.0309

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.0303

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000783

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00197 AC: 2875 AN: 1461786 Hom.: 30 Cov.: 32 AF XY: 0.00188 AC XY: 1367 AN XY: 727198

African (AFR) AF: 0.0314 AC: 1051 AN: 33480

American (AMR) AF: 0.00179 AC: 80 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0298 AC: 779 AN: 26136

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.000563 AC: 626 AN: 1111958

Other (OTH) AF: 0.00520 AC: 314 AN: 60394

GnomAD4 genome AF: 0.0103 AC: 1563 AN: 152174 Hom.: 28 Cov.: 32 AF XY: 0.00993 AC XY: 739 AN XY: 74404

African (AFR) AF: 0.0325 AC: 1347 AN: 41474

American (AMR) AF: 0.00274 AC: 42 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0329 AC: 114 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68016

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00744 Hom.: 7

Bravo AF: 0.0112

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.2
DANN	Benign	0.80
PhyloP100		-0.99
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs115847549; hg19: chr21-45929192;