chr21-44499743-CCCACCTGGCCACCCCAGTTGCTGCCGGGCAGCCGCGGCCTCAGCGTGTCCTCAG-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_144991.3(TSPEAR):​c.1996_*39delCTGAGGACACGCTGAGGCCGCGGCTGCCCGGCAGCAACTGGGGTGGCCAGGTGG​(p.Leu666_Ter670del) variant causes a stop lost, conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000291 in 1,374,138 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

TSPEAR
NM_144991.3 stop_lost, conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.386
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1
Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TSPEARNM_144991.3 linkuse as main transcriptc.1996_*39delCTGAGGACACGCTGAGGCCGCGGCTGCCCGGCAGCAACTGGGGTGGCCAGGTGG p.Leu666_Ter670del stop_lost, conservative_inframe_deletion 12/12 ENST00000323084.9 NP_659428.2 Q8WU66-1
TSPEARNM_144991.3 linkuse as main transcriptc.1995_*39delCTGAGGACACGCTGAGGCCGCGGCTGCCCGGCAGCAACTGGGGTGGCCAGGTGG 3_prime_UTR_variant 12/12 ENST00000323084.9 NP_659428.2 Q8WU66-1
TSPEARNM_001272037.2 linkuse as main transcriptc.1792_*39delCTGAGGACACGCTGAGGCCGCGGCTGCCCGGCAGCAACTGGGGTGGCCAGGTGG p.Leu598_Ter602del stop_lost, conservative_inframe_deletion 13/13 NP_001258966.1 Q8WU66
TSPEARNM_001272037.2 linkuse as main transcriptc.1791_*39delCTGAGGACACGCTGAGGCCGCGGCTGCCCGGCAGCAACTGGGGTGGCCAGGTGG 3_prime_UTR_variant 13/13 NP_001258966.1 Q8WU66

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TSPEARENST00000323084.9 linkuse as main transcriptc.1996_*39delCTGAGGACACGCTGAGGCCGCGGCTGCCCGGCAGCAACTGGGGTGGCCAGGTGG p.Leu666_Ter670del stop_lost, conservative_inframe_deletion 12/121 NM_144991.3 ENSP00000321987.4 Q8WU66-1
TSPEARENST00000323084 linkuse as main transcriptc.1995_*39delCTGAGGACACGCTGAGGCCGCGGCTGCCCGGCAGCAACTGGGGTGGCCAGGTGG 3_prime_UTR_variant 12/121 NM_144991.3 ENSP00000321987.4 Q8WU66-1
TSPEARENST00000642437.1 linkuse as main transcriptn.*1941_*1994delCTGAGGACACGCTGAGGCCGCGGCTGCCCGGCAGCAACTGGGGTGGCCAGGTGG non_coding_transcript_exon_variant 13/13 ENSP00000496535.1 A0A2R8YFK6
TSPEARENST00000642437.1 linkuse as main transcriptn.*1941_*1994delCTGAGGACACGCTGAGGCCGCGGCTGCCCGGCAGCAACTGGGGTGGCCAGGTGG 3_prime_UTR_variant 13/13 ENSP00000496535.1 A0A2R8YFK6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000291
AC:
4
AN:
1374138
Hom.:
0
AF XY:
0.00000295
AC XY:
2
AN XY:
676940
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:
0.00000374
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

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 submitterclinical testingGeneDxMay 02, 2024Frameshift variant predicted to result in abnormal protein length as the last 4 amino acids are replaced with 50 different amino acids; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-45919626; API