21-44525765-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_144991.3(TSPEAR):c.1224C>G(p.His408Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0609 in 1,614,070 control chromosomes in the GnomAD database, including 3,432 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 217 hom., cov: 33)

Exomes 𝑓: 0.062 ( 3215 hom. )

Consequence

TSPEAR
NM_144991.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.326

Publications

10 publications found

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-AS1 (HGNC:1271): (TSPEAR antisense RNA 1)

TSPEAR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022302568).

BP6

Variant 21-44525765-G-C is Benign according to our data. Variant chr21-44525765-G-C is described in ClinVar as Benign. ClinVar VariationId is 227130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.068 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPEAR	NM_144991.3 link	c.1224C>G	p.His408Gln	missense_variant	Exon 8 of 12	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2 link	c.1020C>G	p.His340Gln	missense_variant	Exon 9 of 13		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPEAR	ENST00000323084.9 link	c.1224C>G	p.His408Gln	missense_variant	Exon 8 of 12	1	NM_144991.3	ENSP00000321987.4

Frequencies

GnomAD3 genomes

AF:

0.0472

AC:

7182

AN:

152106

Hom.:

217

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0123

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0331

Gnomad ASJ

AF:

0.0311

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0193

Gnomad FIN

AF:

0.103

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0697

Gnomad OTH

AF:

0.0417

GnomAD2 exomes

AF:

0.0479

AC:

12045

AN:

251484

AF XY:

0.0483

show subpopulations

Gnomad AFR exome

AF:

0.0105

Gnomad AMR exome

AF:

0.0234

Gnomad ASJ exome

AF:

0.0286

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.103

Gnomad NFE exome

AF:

0.0666

Gnomad OTH exome

AF:

0.0502

GnomAD4 exome

AF:

0.0623

AC:

91140

AN:

1461846

Hom.:

3215

Cov.:

AF XY:

0.0613

AC XY:

44546

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00953

AC:

319

AN:

33480

American (AMR)

AF:

0.0252

AC:

1126

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0293

AC:

767

AN:

26134

East Asian (EAS)

AF:

0.000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0227

AC:

1954

AN:

86258

European-Finnish (FIN)

AF:

0.102

AC:

5424

AN:

53408

Middle Eastern (MID)

AF:

0.0265

AC:

153

AN:

5768

European-Non Finnish (NFE)

AF:

0.0706

AC:

78472

AN:

1111986

Other (OTH)

AF:

0.0483

AC:

2915

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

4814

9628

14443

19257

24071

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2844

5688

8532

11376

14220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0472

AC:

7182

AN:

152224

Hom.:

217

Cov.:

AF XY:

0.0465

AC XY:

3461

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0122

AC:

508

AN:

41544

American (AMR)

AF:

0.0331

AC:

506

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0311

AC:

108

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.0199

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.103

AC:

1094

AN:

10576

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0697

AC:

4739

AN:

68012

Other (OTH)

AF:

0.0412

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

344

689

1033

1378

1722

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0576

Hom.:

101

Bravo

AF:

0.0398

TwinsUK

AF:

0.0688

AC:

255

ALSPAC

AF:

0.0758

AC:

292

ESP6500AA

AF:

0.0134

AC:

ESP6500EA

AF:

0.0647

AC:

556

ExAC

AF:

0.0470

AC:

5703

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.0625

EpiControl

AF:

0.0613

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nov 26, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

His408Gln in exon 8 of TSPEAR: This variant is not expected to have clinical sig nificance because it has been identified in 6.5% (556/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs35028190).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.15

T;T

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.0

.;T

MetaRNN

Benign

0.0022

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L

PhyloP100

0.33

PrimateAI

Benign

0.26

PROVEAN

Benign

0.0

.;N

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;T

Sift4G

Pathogenic

0.0

.;T

Vest4

0.0

ClinPred

0.000023

GERP RS

1.6

Varity_R

0.064

gMVP

0.19

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over