chr12-110614265-C-T

Position:

chr12-110614265-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001173975.3(TCTN1):c.-147C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,595,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TCTN1
NM_001173975.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0420

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.084225774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCTN1	NM_001082538.3 link	c.83C>T	p.Pro28Leu	missense_variant	1/15	ENST00000397659.9	NP_001076007.1	Q2MV58-2B4DIB9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TCTN1	ENST00000397659.9 link	c.83C>T	p.Pro28Leu	missense_variant	1/15	1	NM_001082538.3	ENSP00000380779.4	Q2MV58-2
TCTN1	ENST00000551590.5 link	c.83C>T	p.Pro28Leu	missense_variant	1/15	1		ENSP00000448735.1	Q2MV58-1
TCTN1	ENST00000397655.7 link	c.83C>T	p.Pro28Leu	missense_variant	1/15	1		ENSP00000380775.3	Q2MV58-3
TCTN1	ENST00000397656.8 link	n.83C>T		non_coding_transcript_exon_variant	1/16	2		ENSP00000380776.4	J3KPW2
TCTN1	ENST00000480648.5 link	n.83C>T		non_coding_transcript_exon_variant	1/16	5		ENSP00000437196.1	E9PNE4
TCTN1	ENST00000495659.6 link	n.83C>T		non_coding_transcript_exon_variant	1/15	2		ENSP00000436673.2	E9PIB8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1443104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716204

show subpopulations

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:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 27, 2020

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 output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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 TCTN1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 28 of the TCTN1 protein (p.Pro28Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

.;.;T;.;T;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.78

T;T;T;T;T;T

M_CAP

Benign

0.056

MetaRNN

Benign

0.084

T;T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.3

.;.;L;L;.;L

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.6

.;.;D;N;.;D

REVEL

Benign

0.17

Sift

Benign

0.091

.;.;T;T;.;T

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

0.027

B;.;B;B;.;B

Vest4

0.068

MutPred

0.51

Gain of catalytic residue at Q23 (P = 0.0073);Gain of catalytic residue at Q23 (P = 0.0073);Gain of catalytic residue at Q23 (P = 0.0073);Gain of catalytic residue at Q23 (P = 0.0073);Gain of catalytic residue at Q23 (P = 0.0073);Gain of catalytic residue at Q23 (P = 0.0073);

MVP

0.63

MPC

0.20

ClinPred

0.22

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.069

gMVP

0.41

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over