12-110614201-C-T

Variant summary

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

The NM_001082538.3(TCTN1):c.19C>T(p.Pro7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,419,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P7L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TCTN1 NM_001082538.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.152

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12467384).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCTN1	NM_001082538.3	c.19C>T	p.Pro7Ser	missense_variant	1/15	ENST00000397659.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCTN1	ENST00000397659.9	c.19C>T	p.Pro7Ser	missense_variant	1/15	1	NM_001082538.3	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1419150 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 702174

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: 0.0000170

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1489973). This variant has not been reported in the literature in individuals affected with TCTN1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 7 of the TCTN1 protein (p.Pro7Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	8.1
Dann	Uncertain	0.98
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.78	T;T;T;T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.12	T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.50	T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.27	B;.;B;B;.;B
Vest4		0.13
MutPred		0.35		Loss of sheet (P = 7e-04);Loss of sheet (P = 7e-04);Loss of sheet (P = 7e-04);Loss of sheet (P = 7e-04);Loss of sheet (P = 7e-04);Loss of sheet (P = 7e-04);
MVP		0.72
MPC		0.19
ClinPred		0.15	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.10
gMVP		0.43

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: chr12-111052006;