rs117791519

chr21-44529886-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.702C>T(p.Asn234=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00567 in 1,613,222 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (27 hom.)
• Consequence: TSPEAR NM_144991.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.06

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]

LOC124905038 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 21-44529886-G-A is Benign according to our data. Variant chr21-44529886-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0045 (686/152340) while in subpopulation NFE AF= 0.00817 (556/68022). AF 95% confidence interval is 0.00761. There are 5 homozygotes in gnomad4. There are 348 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPEAR	NM_144991.3	c.702C>T	p.Asn234=	synonymous_variant	5/12	ENST00000323084.9
LOC124905038	XR_007067905.1	n.2378G>A		non_coding_transcript_exon_variant	1/2
TSPEAR	NM_001272037.2	c.498C>T	p.Asn166=	synonymous_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPEAR	ENST00000323084.9	c.702C>T	p.Asn234=	synonymous_variant	5/12	1	NM_144991.3	P1
TSPEAR	ENST00000397916.1	n.657C>T		non_coding_transcript_exon_variant	5/11	1
TSPEAR	ENST00000642437.1	c.*647C>T		3_prime_UTR_variant, NMD_transcript_variant	6/13

Frequencies

GnomAD3 genomes AF: 0.00450 AC: 685 AN: 152222 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00817

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00445 AC: 1113 AN: 249956 Hom.: 2 AF XY: 0.00433 AC XY: 586 AN XY: 135304

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00242

Gnomad NFE exome AF: 0.00842

Gnomad OTH exome AF: 0.00410

GnomAD4 exome AF: 0.00579 AC: 8456 AN: 1460882 Hom.: 27 Cov.: 31 AF XY: 0.00550 AC XY: 3999 AN XY: 726792

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00306

Gnomad4 NFE exome AF: 0.00713

Gnomad4 OTH exome AF: 0.00421

GnomAD4 genome AF: 0.00450 AC: 686 AN: 152340 Hom.: 5 Cov.: 33 AF XY: 0.00467 AC XY: 348 AN XY: 74498

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00817

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00676 Hom.: 4

Bravo AF: 0.00409

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00660

EpiControl AF: 0.00623

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	TSPEAR: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Asn234Asn in exon 5 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 0.6% (51/8600) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs117791519). -

TSPEAR-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2020

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	-0.85
Cadd	Benign	1.8
Dann	Benign	0.91

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: rs117791519; hg19: chr21-45949769;