10-95664125-G-C

Variant names:

• chr10-95664125-G-C
• rs927310199
• NM_015631.6:c.1766C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015631.6(TCTN3):​c.1766C>G​(p.Ser589Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TCTN3 NM_015631.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.632

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08837104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN3	NM_015631.6	c.1766C>G	p.Ser589Cys	missense_variant	Exon 14 of 14	ENST00000371217.10	NP_056446.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN3	ENST00000371217.10	c.1766C>G	p.Ser589Cys	missense_variant	Exon 14 of 14	1	NM_015631.6	ENSP00000360261.5
TCTN3	ENST00000265993.13	c.1820C>G	p.Ser607Cys	missense_variant	Exon 14 of 14	1		ENSP00000265993.9
TCTN3	ENST00000430368.6	c.1322C>G	p.Ser441Cys	missense_variant	Exon 10 of 10	2		ENSP00000387567.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1766C>G (p.S589C) alteration is located in exon 14 (coding exon 14) of the TCTN3 gene. This alteration results from a C to G substitution at nucleotide position 1766, causing the serine (S) at amino acid position 589 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Orofacial-digital syndrome IV;C3553758:Joubert syndrome 18 Uncertain:1

Aug 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 589 of the TCTN3 protein (p.Ser589Cys). This variant is not present in population databases (gnomAD no frequency). 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: 1448693). 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: "Tolerated"; 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	10
DANN	Benign	0.86
DEOGEN2	Benign	0.0076	T;T;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.51	T;.;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.088	T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	2.0	M;M;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.91	.;.;.;N
REVEL	Benign	0.12
Sift	Benign	0.076	.;.;.;T
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		0.055	B;B;.;.
Vest4		0.18
MutPred		0.44		Gain of helix (P = 0.062);Gain of helix (P = 0.062);.;.;
MVP		0.15
MPC		0.50
ClinPred		0.087	T
GERP RS		1.7
Varity_R		0.035
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs927310199; hg19: chr10-97423882;