rs200042949

Variant names:

• chr10-95685579-T-C
• rs200042949
• NM_015631.6:c.946A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015631.6(TCTN3):​c.946A>G​(p.Thr316Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,551,524 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: TCTN3 NM_015631.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 2.83
• Publications: 4 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03589481).
• BP6: Variant 10-95685579-T-C is Benign according to our data. Variant chr10-95685579-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 540484.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00113 (172/152326) while in subpopulation NFE AF = 0.00222 (151/68016). AF 95% confidence interval is 0.00193. There are 0 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.946A>G	p.Thr316Ala	missense	Exon 8 of 14	NP_056446.4	Q6NUS6-1
	TCTN3	NM_001410982.1		c.888+916A>G		intron	N/A	NP_001397911.1	A0A7P0TB57
	TCTN3	NM_001143973.2		c.651+916A>G		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.946A>G	p.Thr316Ala	missense	Exon 8 of 14	ENSP00000360261.5	Q6NUS6-1
	TCTN3	ENST00000265993.13	TSL:1	c.1000A>G	p.Thr334Ala	missense	Exon 8 of 14	ENSP00000265993.9	A0A0C4DFN5
	TCTN3	ENST00000614499.5	TSL:1	c.1000A>G	p.Thr334Ala	missense	Exon 8 of 14	ENSP00000483364.2	A0A804G9W2

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00222

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000825 AC: 129 AN: 156422 AF XY: 0.000748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.000824

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000535

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.000684

GnomAD4 exome AF: 0.00114 AC: 1599 AN: 1399198 Hom.: 3 Cov.: 30 AF XY: 0.00116 AC XY: 799 AN XY: 690096

African (AFR) AF: 0.0000633 AC: 2 AN: 31596

American (AMR) AF: 0.000196 AC: 7 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 27 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35718

South Asian (SAS) AF: 0.000290 AC: 23 AN: 79230

European-Finnish (FIN) AF: 0.000447 AC: 22 AN: 49242

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5696

European-Non Finnish (NFE) AF: 0.00135 AC: 1457 AN: 1078852

Other (OTH) AF: 0.00103 AC: 60 AN: 57990

GnomAD4 genome AF: 0.00113 AC: 172 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74498

African (AFR) AF: 0.000240 AC: 10 AN: 41590

American (AMR) AF: 0.000131 AC: 2 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00222 AC: 151 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00140 Hom.: 0

Bravo AF: 0.000888

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.00112 AC: 27

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	1	1	Orofacial-digital syndrome IV;C3553758:Joubert syndrome 18 (2)
-	1	-	not specified (1)
-	-	1	TCTN3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.0028
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.8
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.32
Sift	Benign	0.43	T
Sift4G	Uncertain	0.014	D
Polyphen		0.092	B
Vest4		0.24
MVP		0.89
MPC		0.11
ClinPred		0.034	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.36
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200042949; hg19: chr10-97445336;