NM_015631.6:c.283A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_015631.6(TCTN3):​c.283A>C​(p.Thr95Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000415 in 1,551,378 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00044 ( 0 hom. )

Consequence

TCTN3
NM_015631.6 missense

Scores

1
10
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 1.26

Publications

1 publications found
Variant links:
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]
TCTN3 Gene-Disease associations (from GenCC):
  • ciliopathy
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • orofaciodigital syndrome IV
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine
  • Joubert syndrome 18
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • Meckel syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • orofaciodigital syndrome type 6
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TCTN3NM_015631.6 linkc.283A>C p.Thr95Pro missense_variant Exon 2 of 14 ENST00000371217.10 NP_056446.4 Q6NUS6-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TCTN3ENST00000371217.10 linkc.283A>C p.Thr95Pro missense_variant Exon 2 of 14 1 NM_015631.6 ENSP00000360261.5 Q6NUS6-1
TCTN3ENST00000265993.13 linkc.337A>C p.Thr113Pro missense_variant Exon 2 of 14 1 ENSP00000265993.9 A0A0C4DFN5
TCTN3ENST00000430368.6 linkc.283A>C p.Thr95Pro missense_variant Exon 2 of 10 2 ENSP00000387567.1 Q6NUS6-5

Frequencies

GnomAD3 genomes
AF:
0.000211
AC:
32
AN:
151518
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000190
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000354
Gnomad OTH
AF:
0.000482
GnomAD2 exomes
AF:
0.000202
AC:
32
AN:
158046
AF XY:
0.000216
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000412
Gnomad NFE exome
AF:
0.000406
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000437
AC:
612
AN:
1399860
Hom.:
0
Cov.:
32
AF XY:
0.000423
AC XY:
292
AN XY:
690414
show subpopulations
African (AFR)
AF:
0.0000633
AC:
2
AN:
31600
American (AMR)
AF:
0.00
AC:
0
AN:
35708
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25182
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35738
South Asian (SAS)
AF:
0.00
AC:
0
AN:
79236
European-Finnish (FIN)
AF:
0.000647
AC:
32
AN:
49496
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5702
European-Non Finnish (NFE)
AF:
0.000524
AC:
565
AN:
1079074
Other (OTH)
AF:
0.000224
AC:
13
AN:
58124
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
38
76
114
152
190
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
28
56
84
112
140
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000211
AC:
32
AN:
151518
Hom.:
0
Cov.:
32
AF XY:
0.000243
AC XY:
18
AN XY:
73982
show subpopulations
African (AFR)
AF:
0.000121
AC:
5
AN:
41184
American (AMR)
AF:
0.00
AC:
0
AN:
15222
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3460
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5170
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4818
European-Finnish (FIN)
AF:
0.000190
AC:
2
AN:
10518
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000354
AC:
24
AN:
67846
Other (OTH)
AF:
0.000482
AC:
1
AN:
2076
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.517
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000320
Hom.:
0
Bravo
AF:
0.000200
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.000154
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Orofacial-digital syndrome IV;C3553758:Joubert syndrome 18 Uncertain:2
Aug 09, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 95 of the TCTN3 protein (p.Thr95Pro). This variant is present in population databases (rs749447795, gnomAD 0.05%). 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: 242345). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Mar 15, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Uncertain:1Benign:1
Jun 19, 2016
Universitätsklinikum Salzburg, Universitätskinderklinik
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 04, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: TCTN3 c.283A>C (p.Thr95Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 1551378 control chromosomes, predominantly at a frequency of 0.00051 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.29 fold of the estimated maximal expected allele frequency for a pathogenic variant in TCTN3 causing Joubert Syndrome And Related Disorders phenotype (0.0004). c.283A>C has been reported in the literature in individuals affected with Joubert Syndrome And Related Disorders but without sufficient evidence for causality (e.g., Bader_2016, Meerschaut_2022, Phelps_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Joubert Syndrome And Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27377014, 35885997, 28771248). ClinVar contains an entry for this variant (Variation ID: 242345). Based on the evidence outlined above, the variant was classified as likely benign. -

Joubert syndrome 18 Uncertain:1
Oct 19, 2020
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Joubert syndrome (MIM#614815). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition ([#] (40 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 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) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. The variant has previously been classified as a VUS and was identified in individuals where another variant in a different gene was found to be causative of their disease (ClinVar, PMID: 27377014, PMID: 28771248). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.33
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Uncertain
-0.070
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.70
D;D;.;.;.
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Benign
0.28
N
LIST_S2
Benign
0.77
T;.;T;T;T
M_CAP
Benign
0.064
D
MetaRNN
Uncertain
0.47
T;T;T;T;T
MetaSVM
Benign
-0.87
T
MutationAssessor
Pathogenic
3.2
M;M;.;M;M
PhyloP100
1.3
PrimateAI
Uncertain
0.49
T
PROVEAN
Uncertain
-3.3
.;.;.;D;D
REVEL
Uncertain
0.57
Sift
Uncertain
0.019
.;.;.;D;D
Sift4G
Benign
0.062
T;T;T;D;D
Polyphen
1.0
D;D;.;.;D
Vest4
0.43
MVP
0.93
MPC
0.62
ClinPred
0.42
T
GERP RS
3.3
PromoterAI
0.013
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.42
gMVP
0.64
Mutation Taster
=75/25
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs749447795; hg19: chr10-97453207; API