rs41291570

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015631.6(TCTN3):c.224C>T(p.Ala75Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00627 in 1,551,710 control chromosomes in the GnomAD database, including 63 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 ( 61 hom. )

Consequence

TCTN3
NM_015631.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.271

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=0.00509724).

BP6

Variant 10-95693676-G-A is Benign according to our data. Variant chr10-95693676-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 212392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-95693676-G-A is described in Lovd as [Benign]. Variant chr10-95693676-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00452 (688/152324) while in subpopulation SAS AF= 0.0133 (64/4826). AF 95% confidence interval is 0.0107. There are 2 homozygotes in gnomad4. There are 317 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 rank	MANE	Protein	UniProt
TCTN3	NM_015631.6 link	c.224C>T	p.Ala75Val	missense_variant	Exon 1 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.224C>T	p.Ala75Val	missense_variant	Exon 1 of 14	1	NM_015631.6	ENSP00000360261.5	Q6NUS6-1
TCTN3	ENST00000265993.13 link	c.278C>T	p.Ala93Val	missense_variant	Exon 1 of 14	1		ENSP00000265993.9	A0A0C4DFN5
TCTN3	ENST00000430368.6 link	c.224C>T	p.Ala75Val	missense_variant	Exon 1 of 10	2		ENSP00000387567.1	Q6NUS6-5

Frequencies

GnomAD3 genomes

AF:

0.00455

AC:

692

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0135

Gnomad FIN

AF:

0.00556

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00592

Gnomad OTH

AF:

0.00623

GnomAD3 exomes

AF:

0.00717

AC:

1119

AN:

156070

Hom.:

AF XY:

0.00786

AC XY:

651

AN XY:

82784

show subpopulations

Gnomad AFR exome

AF:

0.00101

Gnomad AMR exome

AF:

0.00377

Gnomad ASJ exome

AF:

0.0112

Gnomad EAS exome

AF:

0.0000918

Gnomad SAS exome

AF:

0.0150

Gnomad FIN exome

AF:

0.00928

Gnomad NFE exome

AF:

0.00640

Gnomad OTH exome

AF:

0.00912

GnomAD4 exome

AF:

0.00646

AC:

9035

AN:

1399386

Hom.:

Cov.:

AF XY:

0.00672

AC XY:

4638

AN XY:

690200

show subpopulations

Gnomad4 AFR exome

AF:

0.00206

Gnomad4 AMR exome

AF:

0.00378

Gnomad4 ASJ exome

AF:

0.00998

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.0151

Gnomad4 FIN exome

AF:

0.00974

Gnomad4 NFE exome

AF:

0.00593

Gnomad4 OTH exome

AF:

0.00729

GnomAD4 genome

AF:

0.00452

AC:

688

AN:

152324

Hom.:

Cov.:

AF XY:

0.00426

AC XY:

317

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00154

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00691

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.0133

Gnomad4 FIN

AF:

0.00556

Gnomad4 NFE

AF:

0.00591

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00545

Hom.:

Bravo

AF:

0.00416

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00289

AC:

ESP6500EA

AF:

0.00597

AC:

ExAC

AF:

0.00901

AC:

224

Asia WGS

AF:

0.00462

AC:

AN:

3478

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

Dec 15, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

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. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:4

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TCTN3: BP4, BS1, BS2 -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

0.069

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0038

T;T;.;.;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.0059

LIST_S2

Benign

0.70

T;.;T;T;T

MetaRNN

Benign

0.0051

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;L;.;L;L

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.2

.;.;.;N;N

REVEL

Benign

0.089

Sift

Benign

0.14

.;.;.;T;T

Sift4G

Benign

0.28

T;T;T;T;T

Polyphen

0.0020

B;B;.;.;B

Vest4

0.020

MVP

0.85

MPC

0.11

ClinPred

0.0019

GERP RS

-0.71

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.028

gMVP

0.28

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