rs200042949

Positions:

• chr10-95685579-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015631.6(TCTN3):​c.946A>G​(p.Thr316Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,551,524 control chromosomes in the GnomAD database, including 3 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: TCTN3 NM_015631.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 2.83

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03589481).
• BP6: Variant 10-95685579-T-C is Benign according to our data. Variant chr10-95685579-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 540484.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr10-95685579-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00113 (172/152326) while in subpopulation NFE AF= 0.00222 (151/68016). AF 95% confidence interval is 0.00193. There are 0 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCTN3	NM_015631.6	c.946A>G	p.Thr316Ala	missense_variant	8/14	ENST00000371217.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCTN3	ENST00000371217.10	c.946A>G	p.Thr316Ala	missense_variant	8/14	1	NM_015631.6	P2

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00222

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000825 AC: 129 AN: 156422 Hom.: 0 AF XY: 0.000748 AC XY: 62 AN XY: 82928

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.000824

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000176

Gnomad FIN exome AF: 0.000535

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.000684

GnomAD4 exome AF: 0.00114 AC: 1599 AN: 1399198 Hom.: 3 Cov.: 30 AF XY: 0.00116 AC XY: 799 AN XY: 690096

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.000196

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.000447

Gnomad4 NFE exome AF: 0.00135

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.00113 AC: 172 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74498

Gnomad4 AFR AF: 0.000240

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00222

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.000888

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.00112 AC: 27

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TCTN3: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26582918) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 13, 2022

DNA sequence analysis of the TCTN3 gene demonstrated a sequence change, c.946A>G, in exon 8 that results in an amino acid change, p.Thr316Ala. This sequence change has been described in the gnomAD database with a frequency of 0.20% in the non-Finnish European subpopulation (dbSNP rs200042949). The p.Thr316Ala change affects a moderately conserved amino acid residue located in a domain of the TCTN3 protein that is known to be functional. The p.Thr316Ala substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with TCTN3-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Thr316Ala change remains unknown at this time. -

Orofacial-digital syndrome IV;C3553758:Joubert syndrome 18 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

TCTN3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.0028
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.50	T;.;T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.036	T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.9	L;L;.;L
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.4	.;.;.;N
REVEL	Uncertain	0.32
Sift	Benign	0.43	.;.;.;T
Sift4G	Uncertain	0.014	D;D;D;D
Polyphen		0.092	B;B;.;B
Vest4		0.24
MVP		0.89
MPC		0.11
ClinPred		0.034	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200042949; hg19: chr10-97445336;