10-95693450-T-G

Position:

• chr10-95693450-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (0 hom.)
• Consequence: TCTN3 NM_015631.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.26

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 (HGNC:):

ACMG classification

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	Protein	UniProt
TCTN3	NM_015631.6	c.283A>C	p.Thr95Pro	missense_variant	2/14	ENST00000371217.10	NP_056446.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCTN3	ENST00000371217.10	c.283A>C	p.Thr95Pro	missense_variant	2/14	1	NM_015631.6	ENSP00000360261.5
TCTN3	ENST00000265993.13	c.337A>C	p.Thr113Pro	missense_variant	2/14	1		ENSP00000265993.9
TCTN3	ENST00000430368.6	c.283A>C	p.Thr95Pro	missense_variant	2/10	2		ENSP00000387567.1

Frequencies

GnomAD3 genomes AF: 0.000211 AC: 32 AN: 151518 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000202 AC: 32 AN: 158046 Hom.: 0 AF XY: 0.000216 AC XY: 18 AN XY: 83436

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 SAS 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

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000647

Gnomad4 NFE exome AF: 0.000524

Gnomad4 OTH exome AF: 0.000224

GnomAD4 genome AF: 0.000211 AC: 32 AN: 151518 Hom.: 0 Cov.: 32 AF XY: 0.000243 AC XY: 18 AN XY: 73982

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000190

Gnomad4 NFE AF: 0.000354

Gnomad4 OTH AF: 0.000482

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: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Orofacial-digital syndrome IV;C3553758:Joubert syndrome 18 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 15, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 09, 2022	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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Universitätsklinikum Salzburg, Universitätskinderklinik

Jun 19, 2016

- -

Joubert syndrome 18 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 19, 2020

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
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.42
gMVP		0.64

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

LitVar

Other links and lift over

dbSNP: rs749447795; hg19: chr10-97453207;