chr10-95664075-T-C

Variant names:

• chr10-95664075-T-C
• NM_015631.6:c.1816A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015631.6(TCTN3):​c.1816A>G​(p.Thr606Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TCTN3 NM_015631.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.835
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• orofaciodigital syndrome IV

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, G2P, PanelApp Australia
• Joubert syndrome 18

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• orofaciodigital syndrome type 6

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.069535345).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015631.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN3	NM_015631.6	MANE Select	c.1816A>G	p.Thr606Ala	missense	Exon 14 of 14	NP_056446.4	Q6NUS6-1
	TCTN3	NM_001410982.1		c.1720A>G	p.Thr574Ala	missense	Exon 13 of 13	NP_001397911.1	A0A7P0TB57
	TCTN3	NM_001143973.2		c.1372A>G	p.Thr458Ala	missense	Exon 10 of 10	NP_001137445.1	Q6NUS6-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN3	ENST00000371217.10	TSL:1 MANE Select	c.1816A>G	p.Thr606Ala	missense	Exon 14 of 14	ENSP00000360261.5	Q6NUS6-1
	TCTN3	ENST00000265993.13	TSL:1	c.1870A>G	p.Thr624Ala	missense	Exon 14 of 14	ENSP00000265993.9	A0A0C4DFN5
	TCTN3	ENST00000614499.5	TSL:1	c.1855A>G	p.Thr619Ala	missense	Exon 14 of 14	ENSP00000483364.2	A0A804G9W2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Orofacial-digital syndrome IV;C3553758:Joubert syndrome 18 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.83
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.13	B
Vest4		0.13
MutPred		0.16		Loss of glycosylation at T606 (P = 0.1072)
MVP		0.17
MPC		0.17
ClinPred		0.34	T
GERP RS		3.5
Varity_R		0.081
gMVP		0.56
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

hg19: chr10-97423832;