10-95663951-C-A

Variant names:

• chr10-95663951-C-A
• rs6946
• NM_015631.6:c.*116G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015631.6(TCTN3):​c.*116G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 779,128 control chromosomes in the GnomAD database, including 36,691 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6218 hom., cov: 32)
  • Exomes 𝑓: 0.30 (30473 hom.)
• Consequence: TCTN3 NM_015631.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.290
• Publications: 10 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: 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-95663951-C-A is Benign according to our data. Variant chr10-95663951-C-A is described in ClinVar as [Benign]. Clinvar id is 1236989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN3	NM_015631.6	c.*116G>T		3_prime_UTR_variant	Exon 14 of 14	ENST00000371217.10	NP_056446.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN3	ENST00000371217.10	c.*116G>T		3_prime_UTR_variant	Exon 14 of 14	1	NM_015631.6	ENSP00000360261.5
TCTN3	ENST00000265993.13	c.*116G>T		3_prime_UTR_variant	Exon 14 of 14	1		ENSP00000265993.9
TCTN3	ENST00000430368.6	c.*116G>T		3_prime_UTR_variant	Exon 10 of 10	2		ENSP00000387567.1

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40549 AN: 151882 Hom.: 6225 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.0425

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.249

GnomAD4 exome AF: 0.301 AC: 188550 AN: 627128 Hom.: 30473 Cov.: 8 AF XY: 0.297 AC XY: 98235 AN XY: 330584

African (AFR) AF: 0.134 AC: 2168 AN: 16164

American (AMR) AF: 0.432 AC: 11243 AN: 25998

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 3472 AN: 15666

East Asian (EAS) AF: 0.0474 AC: 1682 AN: 35480

South Asian (SAS) AF: 0.232 AC: 12540 AN: 54148

European-Finnish (FIN) AF: 0.308 AC: 14871 AN: 48284

Middle Eastern (MID) AF: 0.222 AC: 757 AN: 3410

European-Non Finnish (NFE) AF: 0.334 AC: 132415 AN: 395934

Other (OTH) AF: 0.293 AC: 9402 AN: 32044

GnomAD4 genome AF: 0.267 AC: 40540 AN: 152000 Hom.: 6218 Cov.: 32 AF XY: 0.266 AC XY: 19775 AN XY: 74282

African (AFR) AF: 0.137 AC: 5675 AN: 41464

American (AMR) AF: 0.381 AC: 5820 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 752 AN: 3470

East Asian (EAS) AF: 0.0421 AC: 218 AN: 5184

South Asian (SAS) AF: 0.219 AC: 1056 AN: 4816

European-Finnish (FIN) AF: 0.310 AC: 3258 AN: 10520

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.336 AC: 22845 AN: 67966

Other (OTH) AF: 0.246 AC: 520 AN: 2114

Alfa AF: 0.319 Hom.: 3787

Bravo AF: 0.269

Asia WGS AF: 0.129 AC: 453 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.7
DANN	Benign	0.54
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

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: rs6946; hg19: chr10-97423708; COSMIC: COSV56446770;