rs146025689

Positions:

• chr21-44529874-C-T

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.714G>A​(p.Ala238Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,613,622 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00088 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (7 hom.)
• Consequence: TSPEAR NM_144991.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.96

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 21-44529874-C-T is Benign according to our data. Variant chr21-44529874-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 228055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44529874-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.95 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPEAR	NM_144991.3	c.714G>A	p.Ala238Ala	synonymous_variant	5/12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.510G>A	p.Ala170Ala	synonymous_variant	6/13		NP_001258966.1
LOC124905038	XR_007067905.1	n.2366C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9	c.714G>A	p.Ala238Ala	synonymous_variant	5/12	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000397916.1	n.669G>A		non_coding_transcript_exon_variant	5/11	1
TSPEAR	ENST00000642437.1	n.*659G>A		non_coding_transcript_exon_variant	6/13			ENSP00000496535.1
TSPEAR	ENST00000642437.1	n.*659G>A		3_prime_UTR_variant	6/13			ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152194 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00102 AC: 256 AN: 250496 Hom.: 2 AF XY: 0.000966 AC XY: 131 AN XY: 135594

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000327

Gnomad NFE exome AF: 0.000883

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00125 AC: 1829 AN: 1461310 Hom.: 7 Cov.: 31 AF XY: 0.00120 AC XY: 874 AN XY: 726978

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000515

Gnomad4 ASJ exome AF: 0.0113

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000566

Gnomad4 NFE exome AF: 0.00124

Gnomad4 OTH exome AF: 0.00147

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152312 Hom.: 1 Cov.: 33 AF XY: 0.000806 AC XY: 60 AN XY: 74478

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00184 Hom.: 0

Bravo AF: 0.000899

EpiCase AF: 0.000927

EpiControl AF: 0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	TSPEAR: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 16, 2017

p.Ala238Ala in exon 5 of TSPEAR: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 1.1% (113/10126) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http:/ /gnomad.broadinstitute.org/; dbSNP rs146025689). -

TSPEAR-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2022

This variant is classified as 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	-0.67
CADD	Benign	0.29
DANN	Benign	0.92

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: rs146025689; hg19: chr21-45949757; COSMIC: COSV59952202; COSMIC: COSV59952202;