rs200705429
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_015631.6(TCTN3):āc.1271T>Gā(p.Val424Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 32)
Exomes š: 0.000011 ( 0 hom. )
Consequence
TCTN3
NM_015631.6 missense
NM_015631.6 missense
Scores
8
8
Clinical Significance
Conservation
PhyloP100: 2.03
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TCTN3 | NM_015631.6 | c.1271T>G | p.Val424Gly | missense_variant | 11/14 | ENST00000371217.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TCTN3 | ENST00000371217.10 | c.1271T>G | p.Val424Gly | missense_variant | 11/14 | 1 | NM_015631.6 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152110Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251396Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135854
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GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461770Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727180
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152110Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74312
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 06, 2022 | The c.1271T>G (p.V424G) alteration is located in exon 11 (coding exon 11) of the TCTN3 gene. This alteration results from a T to G substitution at nucleotide position 1271, causing the valine (V) at amino acid position 424 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Orofacial-digital syndrome IV;C3553758:Joubert syndrome 18 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 23, 2022 | This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 424 of the TCTN3 protein (p.Val424Gly). This variant is present in population databases (rs200705429, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with TCTN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 473271). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;T;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
Sift4G
Benign
T;T;T;T
Polyphen
P;P;.;.
Vest4
MVP
MPC
0.23
ClinPred
D
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