rs745688122
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Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_015631.6(TCTN3):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,551,544 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
TCTN3
NM_015631.6 start_lost
NM_015631.6 start_lost
Scores
5
5
3
Clinical Significance
Conservation
PhyloP100: 3.48
Genes affected
TCTN3 (HGNC:24519): (tectonic family member 3) This gene encodes a member of the tectonic gene family which functions in Hedgehog signal transduction and development of the neural tube. Mutations in this gene have been associated with Orofaciodigital Syndrome IV and Joubert Syndrom 18. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Sep 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 20 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_015631.6 (TCTN3) was described as [Likely_pathogenic] in ClinVar as 1453812
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 10-95693897-C-T is Pathogenic according to our data. Variant chr10-95693897-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-95693897-C-T is described in Lovd as [Likely_pathogenic]. Variant chr10-95693897-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TCTN3 | NM_015631.6 | c.3G>A | p.Met1? | start_lost | 1/14 | ENST00000371217.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TCTN3 | ENST00000371217.10 | c.3G>A | p.Met1? | start_lost | 1/14 | 1 | NM_015631.6 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152228Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000321 AC: 5AN: 155526Hom.: 0 AF XY: 0.0000242 AC XY: 2AN XY: 82554
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GnomAD4 exome AF: 0.0000164 AC: 23AN: 1399316Hom.: 0 Cov.: 32 AF XY: 0.0000159 AC XY: 11AN XY: 690164
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74370
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Joubert syndrome 18 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins-Biomnis | Dec 13, 2022 | - - |
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
Orofacial-digital syndrome IV;C3553758:Joubert syndrome 18 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change affects the initiator methionine of the TCTN3 mRNA. The next in-frame methionine is located at codon 152. This variant is present in population databases (rs745688122, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with personal or family history of Joubert syndrome (PMID: 26092869; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 217703). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2022 | Also reported with a variant on the opposite allele (in trans) in a patient with features of a TCTN3-related disorder in the published literature (Huljev Frkovic et al., 2022); Initiation codon variant in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26092869, 35170189) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;.;T;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
Sift4G
Pathogenic
D;D;T;D;D
Polyphen
D;D;.;.;D
Vest4
MutPred
Loss of disorder (P = 0.0335);Loss of disorder (P = 0.0335);.;Loss of disorder (P = 0.0335);Loss of disorder (P = 0.0335);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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