rs41299157

chr10-95687353-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_015631.6(TCTN3):c.630T>C(p.Ala210=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00739 in 1,602,830 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (59 hom.)
• Consequence: TCTN3 NM_015631.6 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.726

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 10-95687353-A-G is Benign according to our data. Variant chr10-95687353-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 130578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-95687353-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.726 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00524 (799/152360) while in subpopulation NFE AF= 0.00794 (540/68030). AF 95% confidence interval is 0.00738. There are 4 homozygotes in gnomad4. There are 406 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCTN3	NM_015631.6	c.630T>C	p.Ala210=	splice_region_variant, synonymous_variant	5/14	ENST00000371217.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCTN3	ENST00000371217.10	c.630T>C	p.Ala210=	splice_region_variant, synonymous_variant	5/14	1	NM_015631.6	P2

Frequencies

GnomAD3 genomes AF: 0.00525 AC: 799 AN: 152242 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00794

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00530 AC: 1261 AN: 238126 Hom.: 7 AF XY: 0.00542 AC XY: 701 AN XY: 129374

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.00158

Gnomad ASJ exome AF: 0.000638

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00174

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.00780

Gnomad OTH exome AF: 0.00540

GnomAD4 exome AF: 0.00761 AC: 11038 AN: 1450470 Hom.: 59 Cov.: 31 AF XY: 0.00734 AC XY: 5293 AN XY: 721488

Gnomad4 AFR exome AF: 0.00104

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.000392

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00160

Gnomad4 FIN exome AF: 0.0126

Gnomad4 NFE exome AF: 0.00870

Gnomad4 OTH exome AF: 0.00779

GnomAD4 genome AF: 0.00524 AC: 799 AN: 152360 Hom.: 4 Cov.: 32 AF XY: 0.00545 AC XY: 406 AN XY: 74514

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0126

Gnomad4 NFE AF: 0.00794

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00598 Hom.: 3

Bravo AF: 0.00448

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 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. -
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	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2015	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	TCTN3: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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
BayesDel_noAF	Benign	-0.35
Cadd	Benign	10
Dann	Benign	0.79

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

Other links and lift over

dbSNP: rs41299157; hg19: chr10-97447110;