rs1555270274

Variant names:

• chr10-95687255-T-C
• rs1555270274
• NM_015631.6:c.728A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015631.6(TCTN3):​c.728A>G​(p.Asn243Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,636 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TCTN3 NM_015631.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.26

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN3	NM_015631.6	c.728A>G	p.Asn243Ser	missense_variant	Exon 5 of 14	ENST00000371217.10	NP_056446.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN3	ENST00000371217.10	c.728A>G	p.Asn243Ser	missense_variant	Exon 5 of 14	1	NM_015631.6	ENSP00000360261.5
TCTN3	ENST00000265993.13	c.782A>G	p.Asn261Ser	missense_variant	Exon 5 of 14	1		ENSP00000265993.9
TCTN3	ENST00000430368.6	c.500-96A>G		intron_variant	Intron 3 of 9	2		ENSP00000387567.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461636 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727122

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: 0.0000187

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.728A>G (p.N243S) alteration is located in exon 5 (coding exon 5) of the TCTN3 gene. This alteration results from a A to G substitution at nucleotide position 728, causing the asparagine (N) at amino acid position 243 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Dec 21, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with TCTN3-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with serine at codon 243 of the TCTN3 protein (p.Asn243Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.0011	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;.;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.8	M;M;.;M
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.3	.;.;N;D
REVEL	Uncertain	0.58
Sift	Benign	0.14	.;.;T;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.43
MutPred		0.83		Gain of glycosylation at N243 (P = 0.0242);Gain of glycosylation at N243 (P = 0.0242);.;Gain of glycosylation at N243 (P = 0.0242);
MVP		0.94
MPC		0.48
ClinPred		0.94	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1555270274; hg19: chr10-97447012;