rs141088838

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015631.6(TCTN3):c.1030G>A(p.Gly344Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00633 in 1,613,982 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0065 ( 67 hom. )

Consequence

TCTN3
NM_015631.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.0570

Publications

9 publications found

Variant links:

Genes affected

TCTN3 (HGNC:24519): (tectonic family member 3) This gene encodes a member of the tectonic gene family which functions in Hedgehog signal transduction and development of the neural tube. Mutations in this gene have been associated with Orofaciodigital Syndrome IV and Joubert Syndrom 18. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Sep 2012]

TCTN3 Gene-Disease associations (from GenCC):

ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
orofaciodigital syndrome IV
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine
Joubert syndrome 18
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Meckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
orofaciodigital syndrome type 6
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TCTN3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009601146).

BP6

Variant 10-95684564-C-T is Benign according to our data. Variant chr10-95684564-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 212390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00454 (691/152248) while in subpopulation SAS AF = 0.0133 (64/4822). AF 95% confidence interval is 0.0107. There are 2 homozygotes in GnomAd4. There are 318 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN3	NM_015631.6 link	c.1030G>A	p.Gly344Arg	missense_variant	Exon 9 of 14	ENST00000371217.10	NP_056446.4	Q6NUS6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TCTN3	ENST00000371217.10 link	c.1030G>A	p.Gly344Arg	missense_variant	Exon 9 of 14	1	NM_015631.6	ENSP00000360261.5	Q6NUS6-1
TCTN3	ENST00000265993.13 link	c.1084G>A	p.Gly362Arg	missense_variant	Exon 9 of 14	1		ENSP00000265993.9	A0A0C4DFN5
TCTN3	ENST00000430368.6 link	c.652-935G>A		intron_variant	Intron 5 of 9	2		ENSP00000387567.1	Q6NUS6-5

Frequencies

GnomAD3 genomes

AF:

0.00457

AC:

695

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0135

Gnomad FIN

AF:

0.00566

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00594

Gnomad OTH

AF:

0.00623

GnomAD2 exomes

AF:

0.00687

AC:

1728

AN:

251378

AF XY:

0.00747

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00359

Gnomad ASJ exome

AF:

0.0107

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00869

Gnomad NFE exome

AF:

0.00690

Gnomad OTH exome

AF:

0.00831

GnomAD4 exome

AF:

0.00651

AC:

9523

AN:

1461734

Hom.:

Cov.:

AF XY:

0.00681

AC XY:

4955

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.00215

AC:

AN:

33478

American (AMR)

AF:

0.00367

AC:

164

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00991

AC:

259

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39686

South Asian (SAS)

AF:

0.0152

AC:

1315

AN:

86244

European-Finnish (FIN)

AF:

0.00964

AC:

515

AN:

53414

Middle Eastern (MID)

AF:

0.0151

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00599

AC:

6663

AN:

1111898

Other (OTH)

AF:

0.00739

AC:

446

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

497

994

1490

1987

2484

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00454

AC:

691

AN:

152248

Hom.:

Cov.:

AF XY:

0.00427

AC XY:

318

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

41550

American (AMR)

AF:

0.00294

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00692

AC:

AN:

3470

East Asian (EAS)

AF:

0.000579

AC:

AN:

5182

South Asian (SAS)

AF:

0.0133

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00566

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00593

AC:

403

AN:

68006

Other (OTH)

AF:

0.00569

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

110

146

183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00580

Hom.:

Bravo

AF:

0.00417

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00616

AC:

ExAC

AF:

0.00718

AC:

872

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.00709

EpiControl

AF:

0.00741

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Dec 28, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TCTN3: BP4, BS1, BS2 -

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 15, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 07, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Orofacial-digital syndrome IV;C3553758:Joubert syndrome 18

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.23

CADD

Benign

9.7

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.16

T;T;.;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.69

T;.;T;T

MetaRNN

Benign

0.0096

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.68

N;N;.;N

PhyloP100

-0.057

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.3

.;.;.;N

REVEL

Uncertain

0.38

Sift

Benign

0.48

.;.;.;T

Sift4G

Benign

0.62

T;T;T;T

Polyphen

0.0060

B;B;.;B

Vest4

0.28

MutPred

0.48

Gain of catalytic residue at G344 (P = 0.0312);Gain of catalytic residue at G344 (P = 0.0312);.;Gain of catalytic residue at G344 (P = 0.0312);

MVP

0.79

MPC

0.14

ClinPred

0.0018

GERP RS

-0.79

Varity_R

0.050

gMVP

0.55

Mutation Taster

=96/4

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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rs141088838

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