10-95664117-G-C

Variant names:

• chr10-95664117-G-C
• rs375708075
• NM_015631.6:c.1774C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015631.6(TCTN3):​c.1774C>G​(p.Leu592Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,614,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L592F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: TCTN3 NM_015631.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.147
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028887779).

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.1774C>G	p.Leu592Val	missense	Exon 14 of 14	NP_056446.4	Q6NUS6-1
	TCTN3	NM_001410982.1		c.1678C>G	p.Leu560Val	missense	Exon 13 of 13	NP_001397911.1	A0A7P0TB57
	TCTN3	NM_001143973.2		c.1330C>G	p.Leu444Val	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.1774C>G	p.Leu592Val	missense	Exon 14 of 14	ENSP00000360261.5	Q6NUS6-1
	TCTN3	ENST00000265993.13	TSL:1	c.1828C>G	p.Leu610Val	missense	Exon 14 of 14	ENSP00000265993.9	A0A0C4DFN5
	TCTN3	ENST00000614499.5	TSL:1	c.1813C>G	p.Leu605Val	missense	Exon 14 of 14	ENSP00000483364.2	A0A804G9W2

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000437 AC: 11 AN: 251476 AF XY: 0.0000441

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000154 AC: 225 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.000136 AC XY: 99 AN XY: 727246

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000193 AC: 215 AN: 1112010

Other (OTH) AF: 0.0000993 AC: 6 AN: 60396

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74430

African (AFR) AF: 0.00 AC: 0 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000893 Hom.: 0

Bravo AF: 0.0000869

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	Joubert syndrome 18 (1)
-	1	-	Orofacial-digital syndrome IV;C3553758:Joubert syndrome 18 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.1
DANN	Benign	0.86
DEOGEN2	Benign	0.0093	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.15
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.080
Sift	Benign	0.49	T
Sift4G	Benign	0.33	T
Polyphen		0.0050	B
Vest4		0.072
MVP		0.16
MPC		0.23
ClinPred		0.057	T
GERP RS		-0.92
Varity_R		0.020
gMVP		0.47
Mutation Taster		=90/10	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

dbSNP: rs375708075; hg19: chr10-97423874;