chr3-180603199-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 1 publications found

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]

CCDC39 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 14

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133462.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC14	NM_133462.4	MANE Select	c.362G>A	p.Arg121Gln	missense	Exon 3 of 12	NP_597719.1	Q96N46-1
	TTC14	NM_001288582.2		c.362G>A	p.Arg121Gln	missense	Exon 3 of 13	NP_001275511.1	Q96N46-2
	TTC14	NM_001042601.3		c.362G>A	p.Arg121Gln	missense	Exon 3 of 10	NP_001036066.1	Q96N46-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC14	ENST00000296015.9	TSL:1 MANE Select	c.362G>A	p.Arg121Gln	missense	Exon 3 of 12	ENSP00000296015.4	Q96N46-1
	TTC14	ENST00000382584.8	TSL:1	c.362G>A	p.Arg121Gln	missense	Exon 3 of 13	ENSP00000372027.4	Q96N46-2
	TTC14	ENST00000412756.6	TSL:1	c.362G>A	p.Arg121Gln	missense	Exon 3 of 10	ENSP00000413743.2	Q96N46-3

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

African (AFR) AF: 0.00 AC: 0 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.9	M
PhyloP100		6.3
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.21
Sift	Benign	0.15	T
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.36
MutPred		0.33		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
Mutation Taster		=48/52	disease causing

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