rs55859130

Positions:

chr10-95685600-C-A

Variant summary

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

The ENST00000371217.10(TCTN3):c.925G>T(p.Ala309Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,551,170 control chromosomes in the GnomAD database, including 319 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 28 hom., cov: 32)

Exomes 𝑓: 0.019 ( 291 hom. )

Consequence

TCTN3
ENST00000371217.10 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.300

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=0.0044203997).

BP6

Variant 10-95685600-C-A is Benign according to our data. Variant chr10-95685600-C-A is described in ClinVar as [Benign]. Clinvar id is 130579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-95685600-C-A is described in Lovd as [Likely_benign]. Variant chr10-95685600-C-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0149 (2270/152236) while in subpopulation EAS AF= 0.0377 (195/5178). AF 95% confidence interval is 0.0333. There are 28 homozygotes in gnomad4. There are 1097 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCTN3	NM_015631.6 linkuse as main transcript	c.925G>T	p.Ala309Ser	missense_variant	8/14	ENST00000371217.10	NP_056446.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCTN3	ENST00000371217.10 linkuse as main transcript	c.925G>T	p.Ala309Ser	missense_variant	8/14	1	NM_015631.6	ENSP00000360261	P2	Q6NUS6-1

Frequencies

GnomAD3 genomes

AF:

0.0149

AC:

2273

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00684

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0141

Gnomad ASJ

AF:

0.0311

Gnomad EAS

AF:

0.0374

Gnomad SAS

AF:

0.0174

Gnomad FIN

AF:

0.00386

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0188

Gnomad OTH

AF:

0.0240

GnomAD3 exomes

AF:

0.0174

AC:

2721

AN:

156382

Hom.:

AF XY:

0.0184

AC XY:

1525

AN XY:

82908

show subpopulations

Gnomad AFR exome

AF:

0.00721

Gnomad AMR exome

AF:

0.00912

Gnomad ASJ exome

AF:

0.0313

Gnomad EAS exome

AF:

0.0393

Gnomad SAS exome

AF:

0.0164

Gnomad FIN exome

AF:

0.00410

Gnomad NFE exome

AF:

0.0201

Gnomad OTH exome

AF:

0.0196

GnomAD4 exome

AF:

0.0190

AC:

26538

AN:

1398934

Hom.:

291

Cov.:

AF XY:

0.0192

AC XY:

13278

AN XY:

689962

show subpopulations

Gnomad4 AFR exome

AF:

0.00709

Gnomad4 AMR exome

AF:

0.00944

Gnomad4 ASJ exome

AF:

0.0282

Gnomad4 EAS exome

AF:

0.0367

Gnomad4 SAS exome

AF:

0.0169

Gnomad4 FIN exome

AF:

0.00453

Gnomad4 NFE exome

AF:

0.0195

Gnomad4 OTH exome

AF:

0.0192

GnomAD4 genome

AF:

0.0149

AC:

2270

AN:

152236

Hom.:

Cov.:

AF XY:

0.0147

AC XY:

1097

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00682

Gnomad4 AMR

AF:

0.0141

Gnomad4 ASJ

AF:

0.0311

Gnomad4 EAS

AF:

0.0377

Gnomad4 SAS

AF:

0.0170

Gnomad4 FIN

AF:

0.00386

Gnomad4 NFE

AF:

0.0188

Gnomad4 OTH

AF:

0.0237

Alfa

AF:

0.0203

Hom.:

Bravo

AF:

0.0154

TwinsUK

AF:

0.0186

AC:

ALSPAC

AF:

0.0223

AC:

ESP6500AA

AF:

0.00578

AC:

ESP6500EA

AF:

0.0223

AC:

ExAC

AF:

0.0164

AC:

398

Asia WGS

AF:

0.0200

AC:

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

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2016	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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.35

CADD

Benign

0.58

DANN

Benign

0.21

DEOGEN2

Benign

0.067

T;T;.;.

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.62

T;.;T;T

MetaRNN

Benign

0.0044

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.81

N;N;.;N

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.030

.;.;.;N

REVEL

Benign

0.25

Sift

Benign

0.84

.;.;.;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0010

B;B;.;B

Vest4

0.019

MPC

0.10

ClinPred

0.000039

GERP RS

0.12

Varity_R

0.027

gMVP

0.24

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