10-95684564-C-G

Variant names:

• chr10-95684564-C-G
• NM_015631.6:c.1030G>C
• TCTN3 p.Gly344Arg

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.1030G>C​(p.Gly344Arg) 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. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TCTN3 NM_015631.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0570
• 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: G2P, PanelApp Australia, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
• Joubert syndrome 18

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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=0.17810851).

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.1030G>C	p.Gly344Arg	missense	Exon 9 of 14	NP_056446.4	Q6NUS6-1
	TCTN3	NM_001410982.1		c.949G>C	p.Gly317Arg	missense	Exon 8 of 13	NP_001397911.1	A0A7P0TB57
	TCTN3	NM_001143973.2		c.652-935G>C		intron	N/A	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.1030G>C	p.Gly344Arg	missense	Exon 9 of 14	ENSP00000360261.5	Q6NUS6-1
	TCTN3	ENST00000265993.13	TSL:1	c.1084G>C	p.Gly362Arg	missense	Exon 9 of 14	ENSP00000265993.9	A0A0C4DFN5
	TCTN3	ENST00000614499.5	TSL:1	c.1084G>C	p.Gly362Arg	missense	Exon 9 of 14	ENSP00000483364.2	A0A804G9W2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	0.0043	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	9.5
DANN	Benign	0.76
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.68	N
PhyloP100		-0.057
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.38
Sift	Benign	0.48	T
Sift4G	Benign	0.62	T
Varity_R		0.050
gMVP		0.55
Mutation Taster		=96/4	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr10-97444321;