rs112735071

Positions:

• chr21-44531124-A-G

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.552T>C​(p.Asp184Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,613,712 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (20 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (25 hom.)
• Consequence: TSPEAR NM_144991.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.34

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]

ENSG00000287088 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 21-44531124-A-G is Benign according to our data. Variant chr21-44531124-A-G is described in ClinVar as [Benign]. Clinvar id is 227139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.34 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00873 (1329/152316) while in subpopulation AFR AF= 0.0294 (1222/41560). AF 95% confidence interval is 0.028. There are 20 homozygotes in gnomad4. There are 660 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPEAR	NM_144991.3	c.552T>C	p.Asp184Asp	synonymous_variant	4/12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.348T>C	p.Asp116Asp	synonymous_variant	5/13		NP_001258966.1
LOC124905038	XR_007067905.1	n.3616A>G		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9	c.552T>C	p.Asp184Asp	synonymous_variant	4/12	1	NM_144991.3	ENSP00000321987.4

Frequencies

GnomAD3 genomes AF: 0.00873 AC: 1328 AN: 152198 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00405

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00273 AC: 683 AN: 250084 Hom.: 9 AF XY: 0.00212 AC XY: 287 AN XY: 135466

Gnomad AFR exome AF: 0.0330

Gnomad AMR exome AF: 0.00235

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000417

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00121 AC: 1769 AN: 1461396 Hom.: 25 Cov.: 31 AF XY: 0.00108 AC XY: 787 AN XY: 726942

Gnomad4 AFR exome AF: 0.0316

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000354

Gnomad4 OTH exome AF: 0.00278

GnomAD4 genome AF: 0.00873 AC: 1329 AN: 152316 Hom.: 20 Cov.: 33 AF XY: 0.00886 AC XY: 660 AN XY: 74478

Gnomad4 AFR AF: 0.0294

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00455 Hom.: 4

Bravo AF: 0.0101

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Asp184Asp in exon 4 of TSPEAR: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 3.2% (139/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs112735071). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2018	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. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.21
DANN	Benign	0.28

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: rs112735071; hg19: chr21-45951007;