12-110614185-G-C

Variant names:

• chr12-110614185-G-C
• NM_001082538.3:c.3G>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Supporting PM2 PP5_Moderate

The NM_001082538.3(TCTN1):​c.3G>C​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TCTN1 NM_001082538.3 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.92

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 179 codons. Genomic position: 110628829. Lost 0.301 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-110614185-G-C is Pathogenic according to our data. Variant chr12-110614185-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3764639.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN1	NM_001082538.3	c.3G>C	p.Met1?	start_lost	Exon 1 of 15	ENST00000397659.9	NP_001076007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN1	ENST00000397659.9	c.3G>C	p.Met1?	start_lost	Exon 1 of 15	1	NM_001082538.3	ENSP00000380779.4
TCTN1	ENST00000551590.5	c.3G>C	p.Met1?	start_lost	Exon 1 of 15	1		ENSP00000448735.1
TCTN1	ENST00000397655.7	c.3G>C	p.Met1?	start_lost	Exon 1 of 15	1		ENSP00000380775.3
TCTN1	ENST00000397656.8	n.3G>C		non_coding_transcript_exon_variant	Exon 1 of 16	2		ENSP00000380776.4
TCTN1	ENST00000480648.5	n.3G>C		non_coding_transcript_exon_variant	Exon 1 of 16	5		ENSP00000437196.1
TCTN1	ENST00000495659.6	n.3G>C		non_coding_transcript_exon_variant	Exon 1 of 15	2		ENSP00000436673.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome 13 Pathogenic:1

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.056	.;.;T;.;T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Uncertain	-0.28	T
PROVEAN	Benign	-0.57	.;.;N;N;.;N
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	.;.;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.98	D;.;D;D;.;D
Vest4		0.89
MutPred		0.98		Gain of catalytic residue at L6 (P = 0);Gain of catalytic residue at L6 (P = 0);Gain of catalytic residue at L6 (P = 0);Gain of catalytic residue at L6 (P = 0);Gain of catalytic residue at L6 (P = 0);Gain of catalytic residue at L6 (P = 0);
MVP		0.89
ClinPred		0.98	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.93
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-111051990;