dbSNP rs749447795: TCTN3:p.Thr95Ala (chr10-95693450-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_015631.6(TCTN3):c.283A>G(p.Thr95Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,399,860 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T95P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

TCTN3
NM_015631.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.26

Publications

1 publications found

Variant links:

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, Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine
Joubert syndrome 18
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Meckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
orofaciodigital syndrome type 6
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TCTN3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN3	NM_015631.6 link	c.283A>G	p.Thr95Ala	missense_variant	Exon 2 of 14	ENST00000371217.10	NP_056446.4	Q6NUS6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TCTN3	ENST00000371217.10 link	c.283A>G	p.Thr95Ala	missense_variant	Exon 2 of 14	1	NM_015631.6	ENSP00000360261.5	Q6NUS6-1
TCTN3	ENST00000265993.13 link	c.337A>G	p.Thr113Ala	missense_variant	Exon 2 of 14	1		ENSP00000265993.9	A0A0C4DFN5
TCTN3	ENST00000430368.6 link	c.283A>G	p.Thr95Ala	missense_variant	Exon 2 of 10	2		ENSP00000387567.1	Q6NUS6-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1399860

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690414

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31600

American (AMR)

AF:

0.00

AC:

AN:

35708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079074

Other (OTH)

AF:

0.0000172

AC:

AN:

58124

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.069

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;T;.;.;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.58

T;.;T;T;T

M_CAP

Benign

0.047

MetaRNN

Uncertain

0.62

D;D;D;D;D

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.9

M;M;.;M;M

PhyloP100

1.3

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.0

.;.;.;N;N

REVEL

Uncertain

0.55

Sift

Benign

0.056

.;.;.;T;T

Sift4G

Benign

0.13

T;T;T;T;T

Polyphen

0.99

D;D;.;.;D

Vest4

0.40

MutPred

0.69

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.91

MPC

0.51

ClinPred

0.95

GERP RS

3.3

PromoterAI

0.012

Neutral

(source)

Varity_R

0.082

gMVP

0.50

Mutation Taster

=81/19

polymorphism

(source)

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

Publications

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rs749447795

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over