chr21-44499878-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
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 Likely_benign. Variant got -4 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.012871683).
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:5Benign: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 | - | - - |
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 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis Pathogenic:2
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 | - - |
Tooth agenesis, selective, 10 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 20, 2022 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Nov 24, 2023 | - - |
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