chr21-44567919-G-A

Position:

chr21-44567919-G-A

Variant summary

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

The NM_144991.3(TSPEAR):c.169C>T(p.Arg57Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000746 in 1,605,370 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R57Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 2 hom. )

Consequence

TSPEAR
NM_144991.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 1.62

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=0.02206397).

BP6

Variant 21-44567919-G-A is Benign according to our data. Variant chr21-44567919-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228049.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPEAR	NM_144991.3 linkuse as main transcript	c.169C>T	p.Arg57Trp	missense_variant	2/12	ENST00000323084.9
TSPEAR	NM_001272037.2 linkuse as main transcript	c.-36C>T		5_prime_UTR_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPEAR	ENST00000323084.9 linkuse as main transcript	c.169C>T	p.Arg57Trp	missense_variant	2/12	1	NM_144991.3	P1	Q8WU66-1
TSPEAR	ENST00000397916.1 linkuse as main transcript	n.124C>T		non_coding_transcript_exon_variant	2/11	1
TSPEAR	ENST00000642437.1 linkuse as main transcript	c.*114C>T		3_prime_UTR_variant, NMD_transcript_variant	3/13

Frequencies

GnomAD3 genomes

AF:

0.000888

AC:

135

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00321

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.000961

GnomAD3 exomes

AF:

0.00114

AC:

280

AN:

245780

Hom.:

AF XY:

0.00115

AC XY:

153

AN XY:

132918

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.000152

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.0000554

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00475

Gnomad NFE exome

AF:

0.00149

Gnomad OTH exome

AF:

0.000506

GnomAD4 exome

AF:

0.000732

AC:

1063

AN:

1453152

Hom.:

Cov.:

AF XY:

0.000778

AC XY:

562

AN XY:

722420

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.000137

Gnomad4 ASJ exome

AF:

0.0000775

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00457

Gnomad4 NFE exome

AF:

0.000703

Gnomad4 OTH exome

AF:

0.000533

GnomAD4 genome

AF:

0.000887

AC:

135

AN:

152218

Hom.:

Cov.:

AF XY:

0.000833

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00321

Gnomad4 NFE

AF:

0.00137

Gnomad4 OTH

AF:

0.000951

Alfa

AF:

0.00106

Hom.:

Bravo

AF:

0.000431

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00136

AC:

165

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 27, 2016	p.Arg57Trp in exon 2 of TSPEAR: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (32/6606) of Finnish chromosom es and 0.2% (126/65650) of European chromosomes by the Exome Aggregation Consort ium (ExAC, http://exac.broadinstitute.org; dbSNP rs140542643). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 30, 2015	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

TSPEAR-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2022

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.77

.;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.022

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;M

MutationTaster

Benign

0.64

D;D

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.4

.;D

REVEL

Benign

0.12

Sift

Benign

0.041

.;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.11

B;B

Vest4

0.31

MVP

0.048

MPC

0.052

ClinPred

0.047

GERP RS

2.9

Varity_R

0.069

gMVP

0.67

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