chr21-44567919-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001272037.2(TSPEAR):c.-36C>T variant causes a 5 prime UTR premature start codon gain 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 2 hom. )

Consequence

TSPEAR
NM_001272037.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.62

Publications

5 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 Gene-Disease associations (from GenCC):

ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive nonsyndromic hearing loss 98
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
nonsyndromic genetic hearing loss
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

TSPEAR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 228049.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001272037.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TSPEAR	NM_144991.3	MANE Select	c.169C>T	p.Arg57Trp	missense	Exon 2 of 12	NP_659428.2
TSPEAR	NM_001272037.2		c.-36C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 13	NP_001258966.1
TSPEAR	NM_001272037.2		c.-36C>T		5_prime_UTR	Exon 3 of 13	NP_001258966.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.169C>T	p.Arg57Trp	missense	Exon 2 of 12	ENSP00000321987.4	Q8WU66-1
TSPEAR	ENST00000397916.1	TSL:1	n.124C>T		non_coding_transcript_exon	Exon 2 of 11
TSPEAR	ENST00000943283.1		c.169C>T	p.Arg57Trp	missense	Exon 2 of 13	ENSP00000613342.1

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

GnomAD2 exomes

AF:

0.00114

AC:

280

AN:

245780

AF XY:

0.00115

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 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

African (AFR)

AF:

0.0000300

AC:

AN:

33294

American (AMR)

AF:

0.000137

AC:

AN:

43874

Ashkenazi Jewish (ASJ)

AF:

0.0000775

AC:

AN:

25802

East Asian (EAS)

AF:

0.00

AC:

AN:

39468

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84938

European-Finnish (FIN)

AF:

0.00457

AC:

243

AN:

53218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.000703

AC:

778

AN:

1106818

Other (OTH)

AF:

0.000533

AC:

AN:

60010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

108

163

217

271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000887

AC:

135

AN:

152218

Hom.:

Cov.:

AF XY:

0.000833

AC XY:

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41530

American (AMR)

AF:

0.0000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00321

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00137

AC:

AN:

68004

Other (OTH)

AF:

0.000951

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00105

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

TSPEAR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.77

M_CAP

Benign

0.022

MetaRNN

Benign

0.022

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

1.6

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.12

Sift

Benign

0.041

Sift4G

Pathogenic

0.0010

Polyphen

0.11

Vest4

0.31

MVP

0.048

MPC

0.052

ClinPred

0.047

GERP RS

2.9

Varity_R

0.069

gMVP

0.67

Mutation Taster

=70/30

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over