NM_133462.4:c.680A>G

Variant names:

• chr3-180604586-A-G
• rs376789807
• NM_133462.4:c.680A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_133462.4(TTC14):​c.680A>G​(p.Glu227Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000622 in 1,608,366 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TTC14 NM_133462.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.10
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.680A>G	p.Glu227Gly	missense	Exon 5 of 12	NP_597719.1	Q96N46-1
	TTC14	NM_001288582.2		c.680A>G	p.Glu227Gly	missense	Exon 5 of 13	NP_001275511.1	Q96N46-2
	TTC14	NM_001042601.3		c.680A>G	p.Glu227Gly	missense	Exon 5 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.680A>G	p.Glu227Gly	missense	Exon 5 of 12	ENSP00000296015.4	Q96N46-1
	TTC14	ENST00000382584.8	TSL:1	c.680A>G	p.Glu227Gly	missense	Exon 5 of 13	ENSP00000372027.4	Q96N46-2
	TTC14	ENST00000412756.6	TSL:1	c.680A>G	p.Glu227Gly	missense	Exon 5 of 10	ENSP00000413743.2	Q96N46-3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152130 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 246952 AF XY: 0.0000225

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1456236 Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 724368

African (AFR) AF: 0.00 AC: 0 AN: 33162

American (AMR) AF: 0.00 AC: 0 AN: 43836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39564

South Asian (SAS) AF: 0.00 AC: 0 AN: 84988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5156

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110074

Other (OTH) AF: 0.0000166 AC: 1 AN: 60124

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152130 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74304

African (AFR) AF: 0.0000241 AC: 1 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68012

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

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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	Uncertain	0.34
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.1
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.38
Sift	Benign	0.044	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.43
MVP		0.69
MPC		0.50
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.64
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs376789807; hg19: chr3-180322374;