rs144543830

Variant names:

• chr10-95682678-C-T
• rs144543830
• NM_015631.6:c.1425G>A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_015631.6(TCTN3):​c.1425G>A​(p.Arg475Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000473 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: TCTN3 NM_015631.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.444

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 -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 10-95682678-C-T is Benign according to our data. Variant chr10-95682678-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 383719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-95682678-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.444 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000458 (669/1461706) while in subpopulation MID AF= 0.00225 (13/5766). AF 95% confidence interval is 0.00133. There are 0 homozygotes in gnomad4_exome. There are 348 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN3	NM_015631.6	c.1425G>A	p.Arg475Arg	synonymous_variant	Exon 12 of 14	ENST00000371217.10	NP_056446.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN3	ENST00000371217.10	c.1425G>A	p.Arg475Arg	synonymous_variant	Exon 12 of 14	1	NM_015631.6	ENSP00000360261.5
TCTN3	ENST00000265993.13	c.1479G>A	p.Arg493Arg	synonymous_variant	Exon 12 of 14	1		ENSP00000265993.9
TCTN3	ENST00000430368.6	c.981G>A	p.Arg327Arg	synonymous_variant	Exon 8 of 10	2		ENSP00000387567.1

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000597 AC: 150 AN: 251214 Hom.: 0 AF XY: 0.000655 AC XY: 89 AN XY: 135780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.000590

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000458 AC: 669 AN: 1461706 Hom.: 0 Cov.: 31 AF XY: 0.000479 AC XY: 348 AN XY: 727156

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00237

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.00124

Gnomad4 NFE exome AF: 0.000398

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49 AN XY: 74432

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000594 Hom.: 0

Bravo AF: 0.000491

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000711

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TCTN3: BP4, BP7 -

Jan 15, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TCTN3-related disorder Benign:1

Jun 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.8
DANN	Benign	0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144543830; hg19: chr10-97442435;