rs141088838

Variant names:

• chr10-95684564-C-T
• rs141088838
• NM_015631.6:c.1030G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015631.6(TCTN3):​c.1030G>A​(p.Gly344Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00633 in 1,613,982 control chromosomes in the GnomAD database, including 69 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (67 hom.)
• Consequence: TCTN3 NM_015631.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0570
• Publications: 9 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009601146).
• BP6: Variant 10-95684564-C-T is Benign according to our data. Variant chr10-95684564-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00454 (691/152248) while in subpopulation SAS AF = 0.0133 (64/4822). AF 95% confidence interval is 0.0107. There are 2 homozygotes in GnomAd4. There are 318 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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

Frequencies

GnomAD3 genomes AF: 0.00457 AC: 695 AN: 152130 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.00566

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00594

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00687 AC: 1728 AN: 251378 AF XY: 0.00747

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00359

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00869

Gnomad NFE exome AF: 0.00690

Gnomad OTH exome AF: 0.00831

GnomAD4 exome AF: 0.00651 AC: 9523 AN: 1461734 Hom.: 67 Cov.: 30 AF XY: 0.00681 AC XY: 4955 AN XY: 727164

African (AFR) AF: 0.00215 AC: 72 AN: 33478

American (AMR) AF: 0.00367 AC: 164 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00991 AC: 259 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39686

South Asian (SAS) AF: 0.0152 AC: 1315 AN: 86244

European-Finnish (FIN) AF: 0.00964 AC: 515 AN: 53414

Middle Eastern (MID) AF: 0.0151 AC: 87 AN: 5768

European-Non Finnish (NFE) AF: 0.00599 AC: 6663 AN: 1111898

Other (OTH) AF: 0.00739 AC: 446 AN: 60390

GnomAD4 genome AF: 0.00454 AC: 691 AN: 152248 Hom.: 2 Cov.: 33 AF XY: 0.00427 AC XY: 318 AN XY: 74466

African (AFR) AF: 0.00159 AC: 66 AN: 41550

American (AMR) AF: 0.00294 AC: 45 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4822

European-Finnish (FIN) AF: 0.00566 AC: 60 AN: 10604

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00593 AC: 403 AN: 68006

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00580 Hom.: 8

Bravo AF: 0.00417

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00718 AC: 872

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00709

EpiControl AF: 0.00741

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	1	Orofacial-digital syndrome IV;C3553758:Joubert syndrome 18 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	9.7
DANN	Benign	0.79
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0096	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
Polyphen		0.0060	B
Vest4		0.28
MutPred		0.48		Gain of catalytic residue at G344 (P = 0.0312)
MVP		0.79
MPC		0.14
ClinPred		0.0018	T
GERP RS		-0.79
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

Other links and lift over

dbSNP: rs141088838; hg19: chr10-97444321; COSMIC: COSV105061075; COSMIC: COSV105061075;