rs367543065

Positions:

• chr12-110619834-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001082538.3(TCTN1):​c.221-2A>G variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCTN1 NM_001082538.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.39

Genes affected

TCTN1 (HGNC:26113): (tectonic family member 1) This gene encodes a member of a family of secreted and transmembrane proteins. The orthologous gene in mouse functions downstream of smoothened and rab23 to modulate hedgehog signal transduction. This protein is a component of the tectonic-like complex, which forms a barrier between the ciliary axoneme and the basal body. A mutation in this gene was found in a family with Joubert syndrome-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06745362 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.4, offset of 33, new splice context is: tgtctgtgacttatccccAGcac. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-110619834-A-G is Pathogenic according to our data. Variant chr12-110619834-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 30803.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCTN1	NM_001082538.3	c.221-2A>G		splice_acceptor_variant, intron_variant		ENST00000397659.9	NP_001076007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCTN1	ENST00000397659.9	c.221-2A>G		splice_acceptor_variant, intron_variant		1	NM_001082538.3	ENSP00000380779.4
TCTN1	ENST00000551590.5	c.221-2A>G		splice_acceptor_variant, intron_variant		1		ENSP00000448735.1
TCTN1	ENST00000397655.7	c.221-2A>G		splice_acceptor_variant, intron_variant		1		ENSP00000380775.3
TCTN1	ENST00000397656.8	n.221-2A>G		splice_acceptor_variant, intron_variant		2		ENSP00000380776.4
TCTN1	ENST00000480648.5	n.221-2A>G		splice_acceptor_variant, intron_variant		5		ENSP00000437196.1
TCTN1	ENST00000495659.6	n.282-2A>G		splice_acceptor_variant, intron_variant		2		ENSP00000436673.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2024

TCTN1: PVS1, PM2, PM3 -

Joubert syndrome 13 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 03, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	33
DANN	Uncertain	0.98
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.84	D
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.56		Position offset: 35
DS_AL_spliceai		0.99		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs367543065; hg19: chr12-111057639;