rs143303485

Positions:

chr21-44525804-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000323084.9(TSPEAR):c.1185G>T(p.Glu395Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

TSPEAR
ENST00000323084.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -1.22

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

TSPEAR-AS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.011926204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPEAR	NM_144991.3 linkuse as main transcript	c.1185G>T	p.Glu395Asp	missense_variant	8/12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2 linkuse as main transcript	c.981G>T	p.Glu327Asp	missense_variant	9/13		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9 linkuse as main transcript	c.1185G>T	p.Glu395Asp	missense_variant	8/12	1	NM_144991.3	ENSP00000321987	P1	Q8WU66-1
TSPEAR	ENST00000397916.1 linkuse as main transcript	n.1140G>T		non_coding_transcript_exon_variant	8/11	1
TSPEAR-AS2	ENST00000465978.1 linkuse as main transcript	n.217-20C>A		intron_variant, non_coding_transcript_variant		5
TSPEAR	ENST00000642437.1 linkuse as main transcript	c.*1130G>T		3_prime_UTR_variant, NMD_transcript_variant	9/13			ENSP00000496535

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251460

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.000836

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000210

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000299

Hom.:

Bravo

AF:

0.000196

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 395 of the TSPEAR protein (p.Glu395Asp). This variant is present in population databases (rs143303485, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with TSPEAR-related conditions. ClinVar contains an entry for this variant (Variation ID: 504871). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2021	Reported in a patient with suspected Pendred syndrome in published literature (Nonose et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29739340) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 09, 2017

Variant classified as Uncertain Significance - Favor Benign. The p.Glu395Asp var iant in TSPEAR has not been previously reported in individuals with hearing loss , but was identified in 0.1% (19/24032) of African chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs143303485). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Glutamic acid (Glu) at position 395 is not conserved in mammals or evolutionarily distant species and >10 specie s carry a aspartic acid (Asp) at this position, raising the possibility that thi s change may be tolerated. Additional computational prediction tools support tha t the variant may not impact the protein, though this information is not predict ive enough to rule out pathogenicity. In summary, while the clinical significanc e of the p.Glu395Asp variant is uncertain, these data suggest that it is more li kely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.23

DANN

Benign

0.83

DEOGEN2

Benign

0.16

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.72

.;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.10

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.53

.;N

REVEL

Benign

0.13

Sift

Benign

0.33

.;T

Sift4G

Benign

0.44

.;T

Polyphen

0.0020

B;B

Vest4

0.17

MutPred

0.38

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.048

MPC

0.049

ClinPred

0.080

GERP RS

-7.1

Varity_R

0.050

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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