chr12-110614205-CGCTCCTGGTGGT-C

Position:

• chr12-110614205-CGCTCCTGGTGGT-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_001082538.3(TCTN1):​c.32_43delTGGTGCTCCTGG​(p.Val11_Leu14del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000281 in 1,423,630 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TCTN1 NM_001082538.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 2.47

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]

TCTN1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001082538.3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCTN1	NM_001082538.3	c.32_43delTGGTGCTCCTGG	p.Val11_Leu14del	disruptive_inframe_deletion	1/15	ENST00000397659.9	NP_001076007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCTN1	ENST00000397659.9	c.32_43delTGGTGCTCCTGG	p.Val11_Leu14del	disruptive_inframe_deletion	1/15	1	NM_001082538.3	ENSP00000380779.4
TCTN1	ENST00000551590.5	c.32_43delTGGTGCTCCTGG	p.Val11_Leu14del	disruptive_inframe_deletion	1/15	1		ENSP00000448735.1
TCTN1	ENST00000397655.7	c.32_43delTGGTGCTCCTGG	p.Val11_Leu14del	disruptive_inframe_deletion	1/15	1		ENSP00000380775.3
TCTN1	ENST00000397656.8	n.32_43delTGGTGCTCCTGG		non_coding_transcript_exon_variant	1/16	2		ENSP00000380776.4
TCTN1	ENST00000480648.5	n.32_43delTGGTGCTCCTGG		non_coding_transcript_exon_variant	1/16	5		ENSP00000437196.1
TCTN1	ENST00000495659.6	n.32_43delTGGTGCTCCTGG		non_coding_transcript_exon_variant	1/15	2		ENSP00000436673.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000281 AC: 4 AN: 1423630 Hom.: 0 AF XY: 0.00000426 AC XY: 3 AN XY: 704730

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: 0.00000366

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 13 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Apr 29, 2021

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 21, 2023

Variant summary: TCTN1 c.32_43del12 (p.Val11_Leu14del) results in an in-frame deletion that is predicted to remove four amino acids from the encoded protein. The variant was absent in 183748 control chromosomes (gnomAD). c.32_43del12 has been reported in the literature in at least one homozygous individual affected with Meckel-Gruber syndrome (Shaheen_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance and pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

AiLife Diagnostics, AiLife Diagnostics

Feb 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr12-111052010;