rs140923114

Variant names:

• chr21-44533816-C-T
• rs140923114
• NM_144991.3:c.411G>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.411G>A​(p.Thr137Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,612,532 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00018 (4 hom.)
• Consequence: TSPEAR NM_144991.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.401

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 21-44533816-C-T is Benign according to our data. Variant chr21-44533816-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 504829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.401 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPEAR	NM_144991.3	c.411G>A	p.Thr137Thr	synonymous_variant	Exon 3 of 12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.207G>A	p.Thr69Thr	synonymous_variant	Exon 4 of 13		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9	c.411G>A	p.Thr137Thr	synonymous_variant	Exon 3 of 12	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000397916.1	n.366G>A		non_coding_transcript_exon_variant	Exon 3 of 11	1
TSPEAR	ENST00000642437.1	n.*356G>A		non_coding_transcript_exon_variant	Exon 4 of 13			ENSP00000496535.1
TSPEAR	ENST00000642437.1	n.*356G>A		3_prime_UTR_variant	Exon 4 of 13			ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152114 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000315 AC: 78 AN: 247528 Hom.: 3 AF XY: 0.000430 AC XY: 58 AN XY: 134900

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000198

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000179 AC: 261 AN: 1460300 Hom.: 4 Cov.: 33 AF XY: 0.000252 AC XY: 183 AN XY: 726454

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00176

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000540

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152232 Hom.: 0 Cov.: 30 AF XY: 0.000108 AC XY: 8 AN XY: 74394

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.000144

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jun 09, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Thr137Thr in exon 3 of TSPEAR: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 0.2% (26/16428) S outh Asian chromosomes including 3 homozygotes by the Exome Aggregation Consorti um (ExAC, http://exac.broadinstitute.org; dbSNP rs140923114). -

TSPEAR-related disorder Benign:1

Jun 10, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.2
DANN	Benign	0.77

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: rs140923114; hg19: chr21-45953699; COSMIC: COSV59965817;