rs115847549

chr21-44509309-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_144991.3(TSPEAR):c.1644C>T(p.Tyr548=) 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:3
• Conservation: PhyloP100: -0.986

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 -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 id 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPEAR	NM_144991.3	c.1644C>T	p.Tyr548=	synonymous_variant	10/12	ENST00000323084.9
TSPEAR-AS1	NR_103707.1	n.1272G>A		non_coding_transcript_exon_variant	5/7
TSPEAR	NM_001272037.2	c.1440C>T	p.Tyr480=	synonymous_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPEAR	ENST00000323084.9	c.1644C>T	p.Tyr548=	synonymous_variant	10/12	1	NM_144991.3	P1
TSPEAR	ENST00000397916.1	n.1599C>T		non_coding_transcript_exon_variant	10/11	1
TSPEAR-AS1	ENST00000451035.2	n.827G>A		non_coding_transcript_exon_variant	4/6	5
TSPEAR	ENST00000642437.1	c.*1589C>T		3_prime_UTR_variant, NMD_transcript_variant	11/13

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

GnomAD3 exomes AF: 0.00394 AC: 991 AN: 251282 Hom.: 18 AF XY: 0.00342 AC XY: 465 AN XY: 135854

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 SAS exome AF: 0.00

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

Gnomad4 AFR exome AF: 0.0314

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.0298

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000563

Gnomad4 OTH exome AF: 0.00520

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

Gnomad4 AFR AF: 0.0325

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.0329

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00744 Hom.: 7

Bravo AF: 0.0112

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Tyr548Tyr 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 3.1% (138/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs115847549). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	4.2
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs115847549; hg19: chr21-45929192;