rs141088838

Positions:

chr10-95684564-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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:9

Conservation

PhyloP100: -0.0570

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chr10-95684564-C-T is described in Lovd as [Likely_benign]. Variant chr10-95684564-C-T is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCTN3	NM_015631.6 linkuse as main transcript	c.1030G>A	p.Gly344Arg	missense_variant	9/14	ENST00000371217.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCTN3	ENST00000371217.10 linkuse as main transcript	c.1030G>A	p.Gly344Arg	missense_variant	9/14	1	NM_015631.6	P2	Q6NUS6-1

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

GnomAD3 exomes

AF:

0.00687

AC:

1728

AN:

251378

Hom.:

AF XY:

0.00747

AC XY:

1015

AN XY:

135880

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 SAS exome

AF:

0.0148

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

Gnomad4 AFR exome

AF:

0.00215

Gnomad4 AMR exome

AF:

0.00367

Gnomad4 ASJ exome

AF:

0.00991

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0152

Gnomad4 FIN exome

AF:

0.00964

Gnomad4 NFE exome

AF:

0.00599

Gnomad4 OTH exome

AF:

0.00739

GnomAD4 genome

AF:

0.00454

AC:

691

AN:

152248

Hom.:

Cov.:

AF XY:

0.00427

AC XY:

318

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00159

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00692

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0133

Gnomad4 FIN

AF:

0.00566

Gnomad4 NFE

AF:

0.00593

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00601

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 15, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	TCTN3: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Orofacial-digital syndrome IV;C3553758:Joubert syndrome 18

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

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

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

MutationTaster

Benign

1.0

N;N;N;N

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

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