3-180651538-A-T

Variant names:

• chr3-180651538-A-T
• rs200089274
• NM_181426.2:c.1035-5T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_181426.2(CCDC39):​c.1035-5T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000732 in 1,365,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: CCDC39 NM_181426.2 splice_region, intron
• Scores: Splicing: ADA: 0.9964
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.54
• Publications: 1 publications found

Genes affected

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: ClinGen, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000145075 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC39	NM_181426.2	c.1035-5T>A		splice_region_variant, intron_variant	Intron 8 of 19	ENST00000476379.6	NP_852091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC39	ENST00000476379.6	c.1035-5T>A		splice_region_variant, intron_variant	Intron 8 of 19	2	NM_181426.2	ENSP00000417960.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000746 AC: 1 AN: 134076 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000596

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: 7.32e-7 AC: 1 AN: 1365648 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 673372

African (AFR) AF: 0.00 AC: 0 AN: 29474

American (AMR) AF: 0.0000369 AC: 1 AN: 27072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24200

East Asian (EAS) AF: 0.00 AC: 0 AN: 35522

South Asian (SAS) AF: 0.00 AC: 0 AN: 71902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5484

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1068272

Other (OTH) AF: 0.00 AC: 0 AN: 56756

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.79
PhyloP100		2.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.72
SpliceAI score (max)		0.14		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: rs200089274; hg19: chr3-180369326;