3-180603109-A-AT

Variant names:

• chr3-180603109-A-AT
• rs557781816
• NM_133462.4:c.287-3dupT

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PVS1_Moderate BP6 BA1

The NM_133462.4(TTC14):​c.287-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,039,566 control chromosomes in the GnomAD database, including 70 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.016 (63 hom., cov: 32)
  • Exomes 𝑓: 0.016 (7 hom.)
• Consequence: TTC14 NM_133462.4 splice_acceptor, intron
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.273

Genes affected

TTC14 (HGNC:24697): (tetratricopeptide repeat domain 14) Predicted to enable nucleic acid binding activity. [provided by Alliance of Genome Resources, Apr 2022]

CCDC39 (HGNC:25244): (coiled-coil domain 39 molecular ruler complex subunit) The protein encoded by this gene is involved in the motility of cilia and flagella. The encoded protein is essential for the assembly of dynein regulatory and inner dynein arm complexes, which regulate ciliary beat. Defects in this gene are a cause of primary ciliary dyskinesia type 14 (CILD14). [provided by RefSeq, Jul 2011]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08646779 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.5, offset of 0 (no position change), new splice context is: gttaatttttttttttttAGatc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 3-180603109-A-AT is Benign according to our data. Variant chr3-180603109-A-AT is described in ClinVar as [Benign]. Clinvar id is 3059709.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC14	NM_133462.4	c.287-3dupT		splice_acceptor_variant, intron_variant	Intron 2 of 11	ENST00000296015.9	NP_597719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC14	ENST00000296015.9	c.287-15_287-14insT		intron_variant	Intron 2 of 11	1	NM_133462.4	ENSP00000296015.4

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2357 AN: 147534 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0538

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00570

Gnomad ASJ AF: 0.00528

Gnomad EAS AF: 0.00294

Gnomad SAS AF: 0.000643

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.000437

Gnomad OTH AF: 0.0110

GnomAD4 exome AF: 0.0163 AC: 14526 AN: 891966 Hom.: 7 Cov.: 26 AF XY: 0.0157 AC XY: 7013 AN XY: 446658

Gnomad4 AFR exome AF: 0.0889

Gnomad4 AMR exome AF: 0.0188

Gnomad4 ASJ exome AF: 0.0230

Gnomad4 EAS exome AF: 0.0108

Gnomad4 SAS exome AF: 0.0143

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.0141

Gnomad4 OTH exome AF: 0.0193

GnomAD4 genome AF: 0.0160 AC: 2358 AN: 147600 Hom.: 63 Cov.: 32 AF XY: 0.0156 AC XY: 1118 AN XY: 71894

Gnomad4 AFR AF: 0.0537

Gnomad4 AMR AF: 0.00569

Gnomad4 ASJ AF: 0.00528

Gnomad4 EAS AF: 0.00295

Gnomad4 SAS AF: 0.000215

Gnomad4 FIN AF: 0.000943

Gnomad4 NFE AF: 0.000437

Gnomad4 OTH AF: 0.0119

Bravo AF: 0.0183

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TTC14-related disorder Benign:1

Sep 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BranchPoint Hunter		2.0

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

LitVar

Other links and lift over

dbSNP: rs557781816; hg19: chr3-180320897;