3-180603199-G-A

Variant names:

• chr3-180603199-G-A
• rs759235167
• NM_133462.4:c.362G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_133462.4(TTC14):​c.362G>A​(p.Arg121Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TTC14 NM_133462.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.28

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28009266).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC14	NM_133462.4	c.362G>A	p.Arg121Gln	missense_variant	Exon 3 of 12	ENST00000296015.9	NP_597719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC14	ENST00000296015.9	c.362G>A	p.Arg121Gln	missense_variant	Exon 3 of 12	1	NM_133462.4	ENSP00000296015.4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152008 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152008 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74228

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.362G>A (p.R121Q) alteration is located in exon 3 (coding exon 3) of the TTC14 gene. This alteration results from a G to A substitution at nucleotide position 362, causing the arginine (R) at amino acid position 121 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.030	T;.;.;.;.;T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D;.;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.28	T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.9	M;.;M;M;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.24	N;N;N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.15	T;T;D;T;T;D
Sift4G	Uncertain	0.010	D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.36
MutPred		0.33		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);.;.;
MVP		0.56
MPC		0.20
ClinPred		0.92	D
GERP RS		5.7
Varity_R		0.21
gMVP		0.63

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: rs759235167; hg19: chr3-180320987; COSMIC: COSV104608404; COSMIC: COSV104608404;