rs148713881

chr21-44533693-C-T

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.534G>A(p.Pro178=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,607,120 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (17 hom., cov: 30)
  • Exomes 𝑓: 0.00079 (11 hom.)
• Consequence: TSPEAR NM_144991.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.316

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 21-44533693-C-T is Benign according to our data. Variant chr21-44533693-C-T is described in ClinVar as [Benign]. Clinvar id is 227137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.316 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00813 (1238/152318) while in subpopulation AFR AF= 0.0287 (1195/41570). AF 95% confidence interval is 0.0274. There are 17 homozygotes in gnomad4. There are 573 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPEAR	NM_144991.3	c.534G>A	p.Pro178=	synonymous_variant	3/12	ENST00000323084.9
TSPEAR	NM_001272037.2	c.330G>A	p.Pro110=	synonymous_variant	4/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPEAR	ENST00000323084.9	c.534G>A	p.Pro178=	synonymous_variant	3/12	1	NM_144991.3	P1
TSPEAR	ENST00000397916.1	n.489G>A		non_coding_transcript_exon_variant	3/11	1
TSPEAR	ENST00000642437.1	c.*479G>A		3_prime_UTR_variant, NMD_transcript_variant	4/13

Frequencies

GnomAD3 genomes AF: 0.00813 AC: 1238 AN: 152200 Hom.: 17 Cov.: 30

Gnomad AFR AF: 0.0288

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00203 AC: 488 AN: 240730 Hom.: 6 AF XY: 0.00153 AC XY: 202 AN XY: 132070

Gnomad AFR exome AF: 0.0280

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.000788 AC: 1147 AN: 1454802 Hom.: 11 Cov.: 32 AF XY: 0.000688 AC XY: 497 AN XY: 722880

Gnomad4 AFR exome AF: 0.0272

Gnomad4 AMR exome AF: 0.00126

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000759

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.0000196

Gnomad4 NFE exome AF: 0.0000586

Gnomad4 OTH exome AF: 0.00175

GnomAD4 genome AF: 0.00813 AC: 1238 AN: 152318 Hom.: 17 Cov.: 30 AF XY: 0.00769 AC XY: 573 AN XY: 74466

Gnomad4 AFR AF: 0.0287

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00447 Hom.: 1

Bravo AF: 0.00902

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Pro178Pro in exon 3 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 2.4% (104/4358) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs148713881). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	7.0
Dann	Benign	0.60

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: rs148713881; hg19: chr21-45953576; COSMIC: COSV59969913;