rs876658039

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_144991.3(TSPEAR):​c.1864G>A​(p.Gly622Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,452,894 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: 6.9e-7 ( 0 hom. )

Consequence

TSPEAR
NM_144991.3 missense

Scores

7
10
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TSPEARNM_144991.3 linkuse as main transcriptc.1864G>A p.Gly622Ser missense_variant 12/12 ENST00000323084.9 NP_659428.2 Q8WU66-1
TSPEARNM_001272037.2 linkuse as main transcriptc.1660G>A p.Gly554Ser missense_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.1864G>A p.Gly622Ser missense_variant 12/121 NM_144991.3 ENSP00000321987.4 Q8WU66-1
TSPEARENST00000642437.1 linkuse as main transcriptn.*1809G>A non_coding_transcript_exon_variant 13/13 ENSP00000496535.1 A0A2R8YFK6
TSPEARENST00000642437.1 linkuse as main transcriptn.*1809G>A 3_prime_UTR_variant 13/13 ENSP00000496535.1 A0A2R8YFK6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.88e-7
AC:
1
AN:
1452894
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
722596
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000227
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:
0.00
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 specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 23, 2015The p.Gly622Ser variant in TSPEAR has not been previously reported in individual s with hearing loss and data from large population studies is insufficient to as sess the frequency of this variant. Computational prediction tools and conservat ion analyses do not provide strong support for or against an impact to the prote in. In summary, the clinical significance of the p.Gly622Ser variant is uncertai n. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.54
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.050
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.51
D;D
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.96
.;D
M_CAP
Pathogenic
0.37
D
MetaRNN
Pathogenic
0.91
D;D
MetaSVM
Uncertain
0.29
D
MutationAssessor
Pathogenic
3.0
M;M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.73
T
PROVEAN
Uncertain
-2.7
.;D
REVEL
Pathogenic
0.65
Sift
Benign
0.11
.;T
Sift4G
Pathogenic
0.0
.;D
Polyphen
1.0
D;D
Vest4
0.73
MutPred
0.77
Loss of catalytic residue at G622 (P = 0.0211);Loss of catalytic residue at G622 (P = 0.0211);
MVP
0.87
MPC
0.34
ClinPred
0.98
D
GERP RS
4.3
Varity_R
0.37
gMVP
0.52

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.

Other links and lift over

dbSNP: rs876658039; hg19: chr21-45919812; API