rs138480801
Positions:
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_144991.3(TSPEAR):c.1915G>A(p.Asp639Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00379 in 1,606,932 control chromosomes in the GnomAD database, including 19 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 0.0023 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0039 ( 18 hom. )
Consequence
TSPEAR
NM_144991.3 missense
NM_144991.3 missense
Scores
4
4
6
Clinical Significance
Conservation
PhyloP100: 7.10
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 Benign. Variant got -8 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.012871683).
BS2
?
High Homozygotes in GnomAdExome4 at 18 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSPEAR | NM_144991.3 | c.1915G>A | p.Asp639Asn | missense_variant | 12/12 | ENST00000323084.9 | |
TSPEAR | NM_001272037.2 | c.1711G>A | p.Asp571Asn | missense_variant | 13/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSPEAR | ENST00000323084.9 | c.1915G>A | p.Asp639Asn | missense_variant | 12/12 | 1 | NM_144991.3 | P1 | |
TSPEAR | ENST00000642437.1 | c.*1860G>A | 3_prime_UTR_variant, NMD_transcript_variant | 13/13 |
Frequencies
GnomAD3 genomes ? AF: 0.00229 AC: 348AN: 152228Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00229 AC: 533AN: 232456Hom.: 1 AF XY: 0.00231 AC XY: 295AN XY: 127430
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GnomAD4 exome AF: 0.00394 AC: 5738AN: 1454586Hom.: 18 Cov.: 31 AF XY: 0.00379 AC XY: 2743AN XY: 723268
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GnomAD4 genome ? AF: 0.00228 AC: 348AN: 152346Hom.: 1 Cov.: 33 AF XY: 0.00205 AC XY: 153AN XY: 74496
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ESP6500AA
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:6Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:2Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | TSPEAR: BS2 - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 06, 2019 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 11, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30046887, 27736875, 34042254, 25855803, 33144682, 37009414) - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2024 | - - |
Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis Pathogenic:2Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 05, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | research | Duke University Health System Sequencing Clinic, Duke University Health System | Apr 20, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Dec 21, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with tooth agenesis, selective, 10 (MIM#620173) and ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis (MIM#618180). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (592 heterozygotes, 1 homozygote). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as benign, likely benign, a VUS and pathogenic by clinical laboratories in ClinVar. The variant has also been observed as compound heterozygous or homozygous in eight families with hypodontia and ectodermal dysplasia in the literature, and was classified as a VUS or as likely pathogenic (PMID: 34042254, 27736875, 37009414). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Tooth agenesis, selective, 10 Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Nov 24, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 20, 2022 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 16, 2018 | - - |
Autosomal recessive nonsyndromic hearing loss 98 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 18, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
TSPEAR-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 24, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 07, 2016 | p.Asp639Asn in exon 12 of TSPEAR: This variant is not expected to have clinical significance because it has been identified in 0.5% (214/39556) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs138480801). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
Polyphen
D;D
Vest4
0.64
MVP
MPC
0.33
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at