chr21-44533884-C-T

Position:

chr21-44533884-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_144991.3(TSPEAR):c.343G>A(p.Asp115Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000974 in 1,611,820 control chromosomes in the GnomAD database, including 11 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 ( 2 hom., cov: 29)

Exomes 𝑓: 0.00088 ( 9 hom. )

Consequence

TSPEAR
NM_144991.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.775

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:

TSPEAR (HGNC:):

TSPEAR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003951758).

BP6

Variant 21-44533884-C-T is Benign according to our data. Variant chr21-44533884-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504830.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}. Variant chr21-44533884-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000882 (1288/1460264) while in subpopulation MID AF= 0.0236 (136/5768). AF 95% confidence interval is 0.0204. There are 9 homozygotes in gnomad4_exome. There are 644 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPEAR	NM_144991.3 linkuse as main transcript	c.343G>A	p.Asp115Asn	missense_variant	3/12	ENST00000323084.9	NP_659428.2	Q8WU66-1
TSPEAR	NM_001272037.2 linkuse as main transcript	c.139G>A	p.Asp47Asn	missense_variant	4/13		NP_001258966.1	Q8WU66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TSPEAR	ENST00000323084.9 linkuse as main transcript	c.343G>A	p.Asp115Asn	missense_variant	3/12	1	NM_144991.3	ENSP00000321987.4	Q8WU66-1
TSPEAR	ENST00000397916.1 linkuse as main transcript	n.298G>A		non_coding_transcript_exon_variant	3/11	1
TSPEAR	ENST00000642437.1 linkuse as main transcript	n.*288G>A		non_coding_transcript_exon_variant	4/13			ENSP00000496535.1	A0A2R8YFK6
TSPEAR	ENST00000642437.1 linkuse as main transcript	n.*288G>A		3_prime_UTR_variant	4/13			ENSP00000496535.1	A0A2R8YFK6

Frequencies

GnomAD3 genomes

AF:

0.00182

AC:

275

AN:

151440

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00425

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00158

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000629

Gnomad FIN

AF:

0.0000947

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000766

Gnomad OTH

AF:

0.00530

GnomAD3 exomes

AF:

0.00118

AC:

290

AN:

246454

Hom.:

AF XY:

0.00118

AC XY:

159

AN XY:

134350

show subpopulations

Gnomad AFR exome

AF:

0.00405

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.000403

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.00150

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00108

Gnomad OTH exome

AF:

0.00298

GnomAD4 exome

AF:

0.000882

AC:

1288

AN:

1460264

Hom.:

Cov.:

AF XY:

0.000887

AC XY:

644

AN XY:

726438

show subpopulations

Gnomad4 AFR exome

AF:

0.00544

Gnomad4 AMR exome

AF:

0.00127

Gnomad4 ASJ exome

AF:

0.000613

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00152

Gnomad4 FIN exome

AF:

0.0000384

Gnomad4 NFE exome

AF:

0.000571

Gnomad4 OTH exome

AF:

0.00212

GnomAD4 genome

AF:

0.00186

AC:

282

AN:

151556

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

142

AN XY:

73990

show subpopulations

Gnomad4 AFR

AF:

0.00441

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000629

Gnomad4 FIN

AF:

0.0000947

Gnomad4 NFE

AF:

0.000766

Gnomad4 OTH

AF:

0.00524

Alfa

AF:

0.00129

Hom.:

Bravo

AF:

0.00210

ESP6500AA

AF:

0.00456

AC:

ESP6500EA

AF:

0.000931

AC:

ExAC

AF:

0.00115

AC:

139

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	TSPEAR: BS1 -

TSPEAR-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 2023

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

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Asp115Asn in exon 3 of TSPEAR: This variant is not expected to have clinical sig nificance because it has been identified in 0.5% (20/4388) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs144586270). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.77

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.038

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.86

.;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.6

L;L

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.45

.;N

REVEL

Benign

0.045

Sift

Benign

0.46

.;T

Sift4G

Benign

0.53

T;T

Polyphen

0.010

B;B

Vest4

0.21

MVP

0.014

MPC

0.063

ClinPred

0.0017

GERP RS

3.1

Varity_R

0.032

gMVP

0.44

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