rs145478892

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001082538.3(TCTN1):c.298G>A(p.Val100Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

TCTN1
NM_001082538.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: -2.01

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

Joubert syndrome 13
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Meckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TCTN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0093514025).

BP6

Variant 12-110619913-G-A is Benign according to our data. Variant chr12-110619913-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 257400.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000677 (103/152190) while in subpopulation AFR AF = 0.00234 (97/41518). AF 95% confidence interval is 0.00196. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN1	NM_001082538.3 link	c.298G>A	p.Val100Met	missense_variant	Exon 2 of 15	ENST00000397659.9	NP_001076007.1	Q2MV58-2B4DIB9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TCTN1	ENST00000397659.9 link	c.298G>A	p.Val100Met	missense_variant	Exon 2 of 15	1	NM_001082538.3	ENSP00000380779.4	Q2MV58-2
TCTN1	ENST00000551590.5 link	c.298G>A	p.Val100Met	missense_variant	Exon 2 of 15	1		ENSP00000448735.1	Q2MV58-1
TCTN1	ENST00000397655.7 link	c.298G>A	p.Val100Met	missense_variant	Exon 2 of 15	1		ENSP00000380775.3	Q2MV58-3
TCTN1	ENST00000397656.8 link	n.298G>A		non_coding_transcript_exon_variant	Exon 2 of 16	2		ENSP00000380776.4	J3KPW2
TCTN1	ENST00000480648.5 link	n.298G>A		non_coding_transcript_exon_variant	Exon 2 of 16	5		ENSP00000437196.1	E9PNE4
TCTN1	ENST00000495659.6 link	n.*56G>A		non_coding_transcript_exon_variant	Exon 2 of 15	2		ENSP00000436673.2	E9PIB8
TCTN1	ENST00000495659.6 link	n.*56G>A		3_prime_UTR_variant	Exon 2 of 15	2		ENSP00000436673.2	E9PIB8

Frequencies

GnomAD3 genomes

AF:

0.000671

AC:

102

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00232

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000168

AC:

AN:

249582

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.00232

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000937

AC:

137

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00284

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1112000

Other (OTH)

AF:

0.000232

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000677

AC:

103

AN:

152190

Hom.:

Cov.:

AF XY:

0.000753

AC XY:

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00234

AC:

AN:

41518

American (AMR)

AF:

0.0000655

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68022

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000278

Hom.:

Bravo

AF:

0.000699

ESP6500AA

AF:

0.00176

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000149

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 18, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -

Joubert syndrome 13

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 23, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Meckel-Gruber syndrome;C0431399:Joubert syndrome

Benign:1

Jan 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.065

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.17

.;.;T;.;T;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.61

T;T;T;T;T;T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.0094

T;T;T;T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.41

.;.;N;N;.;N;.

PhyloP100

-2.0

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.23

.;.;N;N;.;N;.

REVEL

Benign

0.22

Sift

Benign

0.12

.;.;T;T;.;T;.

Sift4G

Benign

0.20

T;T;T;T;T;T;T

Polyphen

0.39

B;.;B;B;.;B;.

Vest4

0.19

MVP

0.27

MPC

0.20

ClinPred

0.023

GERP RS

-11

Varity_R

0.028

gMVP

0.21

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over