dbSNP rs41299157: TCTN3:p.Ala210Ala (chr10-95687353-A-G) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_015631.6(TCTN3):c.630T>C(p.Ala210Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00739 in 1,602,830 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0076 ( 59 hom. )

Consequence

TCTN3
NM_015631.6 splice_region, synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.726

Publications

3 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: 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

TCTN3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 10-95687353-A-G is Benign according to our data. Variant chr10-95687353-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.726 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00524 (799/152360) while in subpopulation NFE AF = 0.00794 (540/68030). AF 95% confidence interval is 0.00738. There are 4 homozygotes in GnomAd4. There are 406 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCTN3	NM_015631.6	MANE Select	c.630T>C	p.Ala210Ala	splice_region synonymous	Exon 5 of 14	NP_056446.4	Q6NUS6-1
TCTN3	NM_001410982.1		c.630T>C	p.Ala210Ala	splice_region synonymous	Exon 5 of 13	NP_001397911.1	A0A7P0TB57
TCTN3	NM_001143973.2		c.500-194T>C		intron	N/A	NP_001137445.1	Q6NUS6-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCTN3	ENST00000371217.10	TSL:1 MANE Select	c.630T>C	p.Ala210Ala	splice_region synonymous	Exon 5 of 14	ENSP00000360261.5	Q6NUS6-1
TCTN3	ENST00000265993.13	TSL:1	c.684T>C	p.Ala228Ala	splice_region synonymous	Exon 5 of 14	ENSP00000265993.9	A0A0C4DFN5
TCTN3	ENST00000614499.5	TSL:1	c.684T>C	p.Ala228Ala	splice_region synonymous	Exon 5 of 14	ENSP00000483364.2	A0A804G9W2

Frequencies

GnomAD3 genomes

AF:

0.00525

AC:

799

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0126

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00794

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00530

AC:

1261

AN:

238126

AF XY:

0.00542

show subpopulations

Gnomad AFR exome

AF:

0.00138

Gnomad AMR exome

AF:

0.00158

Gnomad ASJ exome

AF:

0.000638

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0118

Gnomad NFE exome

AF:

0.00780

Gnomad OTH exome

AF:

0.00540

GnomAD4 exome

AF:

0.00761

AC:

11038

AN:

1450470

Hom.:

Cov.:

AF XY:

0.00734

AC XY:

5293

AN XY:

721488

show subpopulations

African (AFR)

AF:

0.00104

AC:

AN:

32556

American (AMR)

AF:

0.00177

AC:

AN:

41328

Ashkenazi Jewish (ASJ)

AF:

0.000392

AC:

AN:

25538

East Asian (EAS)

AF:

0.00

AC:

AN:

39646

South Asian (SAS)

AF:

0.00160

AC:

134

AN:

83912

European-Finnish (FIN)

AF:

0.0126

AC:

672

AN:

53228

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00870

AC:

9647

AN:

1108712

Other (OTH)

AF:

0.00779

AC:

466

AN:

59854

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

503

1005

1508

2010

2513

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

368

736

1104

1472

1840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00524

AC:

799

AN:

152360

Hom.:

Cov.:

AF XY:

0.00545

AC XY:

406

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

41588

American (AMR)

AF:

0.00333

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00166

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0126

AC:

134

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00794

AC:

540

AN:

68030

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

117

156

195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00598

Hom.:

Bravo

AF:

0.00448

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (4)

Orofacial-digital syndrome IV;C3553758:Joubert syndrome 18 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

0.73

Mutation Taster

=100/0

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over