Variant chr21-44499873-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_144991.3(TSPEAR):c.1920G>A(p.Trp640Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000275 in 1,453,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

TSPEAR
NM_144991.3 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.41

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 4 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0448 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPEAR	NM_144991.3 linkuse as main transcript	c.1920G>A	p.Trp640Ter	stop_gained	12/12	ENST00000323084.9
TSPEAR	NM_001272037.2 linkuse as main transcript	c.1716G>A	p.Trp572Ter	stop_gained	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPEAR	ENST00000323084.9 linkuse as main transcript	c.1920G>A	p.Trp640Ter	stop_gained	12/12	1	NM_144991.3	P1	Q8WU66-1
TSPEAR	ENST00000642437.1 linkuse as main transcript	c.*1865G>A		3_prime_UTR_variant, NMD_transcript_variant	13/13

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000432

AC:

AN:

231290

Hom.:

AF XY:

0.00000790

AC XY:

AN XY:

126616

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000976

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1453716

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722698

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000361

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

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

GeneDx

Mar 31, 2021

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation as the last 30 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.86

MutationTaster

Benign

1.0

Vest4

0.27

GERP RS

4.3

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