rs150444121

Positions:

• chr21-44521934-C-T
• chr21-44521934-C-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The ENST00000323084.9(TSPEAR):​c.1515G>A​(p.Ser505=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,614,030 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: TSPEAR ENST00000323084.9 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.72

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-AS2 (HGNC:16428): (TSPEAR antisense RNA 2)

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 21-44521934-C-T is Benign according to our data. Variant chr21-44521934-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 228046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44521934-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.72 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPEAR	NM_144991.3	c.1515G>A	p.Ser505=	synonymous_variant	9/12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.1311G>A	p.Ser437=	synonymous_variant	10/13		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9	c.1515G>A	p.Ser505=	synonymous_variant	9/12	1	NM_144991.3	ENSP00000321987	P1
TSPEAR	ENST00000397916.1	n.1470G>A		non_coding_transcript_exon_variant	9/11	1
TSPEAR-AS2	ENST00000465978.1	n.217-3890C>T		intron_variant, non_coding_transcript_variant		5
TSPEAR	ENST00000642437.1	c.*1460G>A		3_prime_UTR_variant, NMD_transcript_variant	10/13			ENSP00000496535

Frequencies

GnomAD3 genomes AF: 0.000743 AC: 113 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000820 AC: 206 AN: 251304 Hom.: 0 AF XY: 0.000714 AC XY: 97 AN XY: 135868

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00121 AC: 1766 AN: 1461794 Hom.: 3 Cov.: 32 AF XY: 0.00113 AC XY: 822 AN XY: 727192

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000469

Gnomad4 NFE exome AF: 0.00151

Gnomad4 OTH exome AF: 0.000894

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.000793 AC XY: 59 AN XY: 74434

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000747 Hom.: 0

Bravo AF: 0.000589

EpiCase AF: 0.00104

EpiControl AF: 0.000889

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2023	- -

TSPEAR-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2019

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). -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 03, 2017

p.Ser505Ser in exon 9 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 0.15% (190/126650 ) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gno mad.broadinstitute.org/; dbSNP rs150444121). -

Autosomal recessive nonsyndromic hearing loss 98;C4748560:Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.3
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs150444121; hg19: chr21-45941817;