dbSNP rs138480801: TSPEAR:p.Asp639Tyr (chr21-44499878-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_144991.3(TSPEAR):c.1915G>T(p.Asp639Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D639N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TSPEAR
NM_144991.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.10

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPEAR	NM_144991.3 link	c.1915G>T	p.Asp639Tyr	missense_variant	Exon 12 of 12	ENST00000323084.9	NP_659428.2	Q8WU66-1
TSPEAR	NM_001272037.2 link	c.1711G>T	p.Asp571Tyr	missense_variant	Exon 13 of 13		NP_001258966.1	Q8WU66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TSPEAR	ENST00000323084.9 link	c.1915G>T	p.Asp639Tyr	missense_variant	Exon 12 of 12	1	NM_144991.3	ENSP00000321987.4	Q8WU66-1
TSPEAR	ENST00000642437.1 link	n.*1860G>T		non_coding_transcript_exon_variant	Exon 13 of 13			ENSP00000496535.1	A0A2R8YFK6
TSPEAR	ENST00000642437.1 link	n.*1860G>T		3_prime_UTR_variant	Exon 13 of 13			ENSP00000496535.1	A0A2R8YFK6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

232456

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1454590

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723268

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33150

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44190

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25888

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39256

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

85146

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

51666

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1109624

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

60060

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

D;D

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.95

.;D

M_CAP

Uncertain

0.091

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.0

.;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.0030

.;D

Sift4G

Pathogenic

0.0

.;D

Polyphen

1.0

D;D

Vest4

0.80

MutPred

0.59

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

MVP

0.27

MPC

0.37

ClinPred

1.0

GERP RS

4.3

Varity_R

0.82

gMVP

0.80

Mutation Taster

=36/64

disease causing

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over