Variant 21-44499821-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_144991.3(TSPEAR):c.1972G>A(p.Glu658Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,430,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

TSPEAR
NM_144991.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.49

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2189433).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPEAR	NM_144991.3 linkuse as main transcript	c.1972G>A	p.Glu658Lys	missense_variant	12/12	ENST00000323084.9	NP_659428.2	Q8WU66-1
TSPEAR	NM_001272037.2 linkuse as main transcript	c.1768G>A	p.Glu590Lys	missense_variant	13/13		NP_001258966.1	Q8WU66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TSPEAR	ENST00000323084.9 linkuse as main transcript	c.1972G>A	p.Glu658Lys	missense_variant	12/12	1	NM_144991.3	ENSP00000321987.4	Q8WU66-1
TSPEAR	ENST00000642437.1 linkuse as main transcript	n.*1917G>A		non_coding_transcript_exon_variant	13/13			ENSP00000496535.1	A0A2R8YFK6
TSPEAR	ENST00000642437.1 linkuse as main transcript	n.*1917G>A		3_prime_UTR_variant	13/13			ENSP00000496535.1	A0A2R8YFK6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000509

AC:

AN:

196414

Hom.:

AF XY:

0.00000942

AC XY:

AN XY:

106194

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000394

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.99e-7

AC:

AN:

1430430

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708854

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000122

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000832

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with TSPEAR-related conditions. This variant is present in population databases (rs782425063, gnomAD 0.004%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 658 of the TSPEAR protein (p.Glu658Lys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.056

T;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.97

.;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;M

MutationTaster

Benign

0.96

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.4

.;N

REVEL

Benign

0.085

Sift

Benign

0.23

.;T

Sift4G

Benign

0.19

.;T

Polyphen

0.87

P;P

Vest4

0.35

MutPred

0.44

Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);

MVP

0.12

MPC

0.21

ClinPred

0.86

GERP RS

4.3

Varity_R

0.25

gMVP

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

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