rs144166142

Positions:

chr21-44533890-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_144991.3(TSPEAR):c.337G>A(p.Glu113Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,611,910 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0025 ( 9 hom. )

Consequence

TSPEAR
NM_144991.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.03

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037771463).

BP6

Variant 21-44533890-C-T is Benign according to our data. Variant chr21-44533890-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228052.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPEAR	NM_144991.3 linkuse as main transcript	c.337G>A	p.Glu113Lys	missense_variant	3/12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2 linkuse as main transcript	c.133G>A	p.Glu45Lys	missense_variant	4/13		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9 linkuse as main transcript	c.337G>A	p.Glu113Lys	missense_variant	3/12	1	NM_144991.3	ENSP00000321987	P1	Q8WU66-1
TSPEAR	ENST00000397916.1 linkuse as main transcript	n.292G>A		non_coding_transcript_exon_variant	3/11	1
TSPEAR	ENST00000642437.1 linkuse as main transcript	c.*282G>A		3_prime_UTR_variant, NMD_transcript_variant	4/13			ENSP00000496535

Frequencies

GnomAD3 genomes

AF:

0.00194

AC:

294

AN:

151620

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000509

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00296

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00175

AC:

430

AN:

246242

Hom.:

AF XY:

0.00180

AC XY:

242

AN XY:

134218

show subpopulations

Gnomad AFR exome

AF:

0.000442

Gnomad AMR exome

AF:

0.00186

Gnomad ASJ exome

AF:

0.00151

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000746

Gnomad NFE exome

AF:

0.00293

Gnomad OTH exome

AF:

0.000996

GnomAD4 exome

AF:

0.00249

AC:

3629

AN:

1460172

Hom.:

Cov.:

AF XY:

0.00249

AC XY:

1806

AN XY:

726362

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.00199

Gnomad4 ASJ exome

AF:

0.00134

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000826

Gnomad4 NFE exome

AF:

0.00297

Gnomad4 OTH exome

AF:

0.00225

GnomAD4 genome

AF:

0.00194

AC:

294

AN:

151738

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

139

AN XY:

74116

show subpopulations

Gnomad4 AFR

AF:

0.000508

Gnomad4 AMR

AF:

0.00308

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00296

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00273

Hom.:

Bravo

AF:

0.00235

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000456

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00164

AC:

198

EpiCase

AF:

0.00376

EpiControl

AF:

0.00350

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	TSPEAR: BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2022

The c.337G>A (p.E113K) alteration is located in exon 3 (coding exon 3) of the TSPEAR gene. This alteration results from a G to A substitution at nucleotide position 337, causing the glutamic acid (E) at amino acid position 113 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

TSPEAR-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2024

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 10, 2017

p.Glu113Lys in exon 3 of TSPEAR: This variant is not expected to have clinical significance because it has been identified in 0.3% (331/123288) of European chr omosomes including 1 homozygote by the Genome Aggregation Database (gnomAD, http ://gnomad.broadinstitute.org; dbSNP rs144166142). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.066

T;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.75

.;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

0.97

D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.2

.;N

REVEL

Benign

0.092

Sift

Benign

0.30

.;T

Sift4G

Benign

0.30

T;T

Polyphen

0.0080

B;B

Vest4

0.23

MVP

0.085

MPC

0.055

ClinPred

0.0042

GERP RS

2.9

Varity_R

0.095

gMVP

0.42

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over