10-95693707-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015631.6(TCTN3):c.193A>C(p.Thr65Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0732 in 1,551,566 control chromosomes in the GnomAD database, including 4,955 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T65I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.10 ( 1074 hom., cov: 32)

Exomes 𝑓: 0.070 ( 3881 hom. )

Consequence

TCTN3
NM_015631.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.939

Publications

14 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=0.001380831).

BP6

Variant 10-95693707-T-G is Benign according to our data. Variant chr10-95693707-T-G is described in ClinVar as Benign. ClinVar VariationId is 130576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN3	NM_015631.6 link	c.193A>C	p.Thr65Pro	missense_variant	Exon 1 of 14	ENST00000371217.10	NP_056446.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TCTN3	ENST00000371217.10 link	c.193A>C	p.Thr65Pro	missense_variant	Exon 1 of 14	1	NM_015631.6	ENSP00000360261.5
TCTN3	ENST00000265993.13 link	c.247A>C	p.Thr83Pro	missense_variant	Exon 1 of 14	1		ENSP00000265993.9
TCTN3	ENST00000430368.6 link	c.193A>C	p.Thr65Pro	missense_variant	Exon 1 of 10	2		ENSP00000387567.1

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15564

AN:

152066

Hom.:

1071

Cov.:

show subpopulations

Gnomad AFR

AF:

0.197

Gnomad AMI

AF:

0.154

Gnomad AMR

AF:

0.0757

Gnomad ASJ

AF:

0.0277

Gnomad EAS

AF:

0.0450

Gnomad SAS

AF:

0.0882

Gnomad FIN

AF:

0.0734

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0643

Gnomad OTH

AF:

0.0882

GnomAD2 exomes

AF:

0.0701

AC:

10915

AN:

155812

AF XY:

0.0680

show subpopulations

Gnomad AFR exome

AF:

0.205

Gnomad AMR exome

AF:

0.0738

Gnomad ASJ exome

AF:

0.0262

Gnomad EAS exome

AF:

0.0330

Gnomad FIN exome

AF:

0.0721

Gnomad NFE exome

AF:

0.0607

Gnomad OTH exome

AF:

0.0598

GnomAD4 exome

AF:

0.0700

AC:

97977

AN:

1399382

Hom.:

3881

Cov.:

AF XY:

0.0699

AC XY:

48221

AN XY:

690198

show subpopulations

African (AFR)

AF:

0.197

AC:

6239

AN:

31598

American (AMR)

AF:

0.0742

AC:

2649

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.0254

AC:

640

AN:

25176

East Asian (EAS)

AF:

0.0576

AC:

2058

AN:

35736

South Asian (SAS)

AF:

0.0785

AC:

6223

AN:

79236

European-Finnish (FIN)

AF:

0.0702

AC:

3457

AN:

49268

Middle Eastern (MID)

AF:

0.0297

AC:

169

AN:

5698

European-Non Finnish (NFE)

AF:

0.0673

AC:

72622

AN:

1078968

Other (OTH)

AF:

0.0676

AC:

3920

AN:

58000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

6047

12093

18140

24186

30233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2844

5688

8532

11376

14220

<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:

0.102

AC:

15581

AN:

152184

Hom.:

1074

Cov.:

AF XY:

0.102

AC XY:

7563

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.197

AC:

8188

AN:

41514

American (AMR)

AF:

0.0756

AC:

1157

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0277

AC:

AN:

3468

East Asian (EAS)

AF:

0.0455

AC:

235

AN:

5168

South Asian (SAS)

AF:

0.0877

AC:

423

AN:

4826

European-Finnish (FIN)

AF:

0.0734

AC:

778

AN:

10604

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0643

AC:

4373

AN:

67994

Other (OTH)

AF:

0.0873

AC:

184

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

698

1397

2095

2794

3492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

320

480

640

800

<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:

0.0711

Hom.:

1763

Bravo

AF:

0.105

TwinsUK

AF:

0.0720

AC:

267

ALSPAC

AF:

0.0682

AC:

263

ESP6500AA

AF:

0.176

AC:

243

ESP6500EA

AF:

0.0713

AC:

227

ExAC

AF:

0.0695

AC:

1706

Asia WGS

AF:

0.0660

AC:

229

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 19, 2016

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.

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

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

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0065

T;T;.;.;.

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.0046

LIST_S2

Benign

0.61

T;.;T;T;T

MetaRNN

Benign

0.0014

T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.8

L;L;.;L;L

PhyloP100

-0.94

PrimateAI

Benign

0.38

PROVEAN

Benign

0.0

.;.;.;N;N

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;.;T;T

Sift4G

Benign

0.20

T;T;T;T;T

Vest4

0.12

ClinPred

0.022

GERP RS

-4.3

PromoterAI

0.0090

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.20

gMVP

0.31

Mutation Taster

=92/8

polymorphism (auto)

(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