chr3-180603174-A-G

Variant names:

• chr3-180603174-A-G
• rs747081027
• NM_133462.4:c.337A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_133462.4(TTC14):​c.337A>G​(p.Met113Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,080 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: TTC14 NM_133462.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.483
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02267015).

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.337A>G	p.Met113Val	missense	Exon 3 of 12	NP_597719.1	Q96N46-1
	TTC14	NM_001288582.2		c.337A>G	p.Met113Val	missense	Exon 3 of 13	NP_001275511.1	Q96N46-2
	TTC14	NM_001042601.3		c.337A>G	p.Met113Val	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.337A>G	p.Met113Val	missense	Exon 3 of 12	ENSP00000296015.4	Q96N46-1
	TTC14	ENST00000382584.8	TSL:1	c.337A>G	p.Met113Val	missense	Exon 3 of 13	ENSP00000372027.4	Q96N46-2
	TTC14	ENST00000412756.6	TSL:1	c.337A>G	p.Met113Val	missense	Exon 3 of 10	ENSP00000413743.2	Q96N46-3

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152130 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000278 AC: 7 AN: 251410 AF XY: 0.00000736

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461832 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727210

African (AFR) AF: 0.000209 AC: 7 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152248 Hom.: 1 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74434

African (AFR) AF: 0.000265 AC: 11 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000412 AC: 5

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	0.053
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.1
DANN	Benign	0.67
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.48
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.068
Sift	Benign	0.29	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.18
MVP		0.15
MPC		0.094
ClinPred		0.0076	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.34
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs747081027; hg19: chr3-180320962; COSMIC: COSV56009873; COSMIC: COSV56009873;