rs1057517693

Positions:

• chr9-78240369-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001330691.3(CEP78):​c.499+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.000000706 in 1,415,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CEP78 NM_001330691.3 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.84

Genes affected

CEP78 (HGNC:25740): (centrosomal protein 78) This gene encodes a centrosomal protein that is both required for the regulation of centrosome-related events during the cell cycle, and required for ciliogenesis. The encoded protein has an N-terminal leucine-rich repeat (LRR) domain with six consecutive LRR repeats, and a C-terminal coiled-coil domain. It interacts with the N-terminal catalytic domain of polo-like kinase 4 (PLK4) and colocalizes with PLK4 to the distal end of the centriole. Naturally occurring mutations in this gene cause defects in primary cilia that result in retinal degeneration and sensorineural hearing loss which are associated with cone-rod degeneration disease as well as Usher syndrome. Low expression of this gene is associated with poor prognosis of colorectal cancer patients. [provided by RefSeq, Mar 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-78240369-G-A is Pathogenic according to our data. Variant chr9-78240369-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 372268.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-78240369-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP78	NM_001330691.3	c.499+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000643273.2	NP_001317620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP78	ENST00000643273.2	c.499+5G>A		splice_donor_5th_base_variant, intron_variant			NM_001330691.3	ENSP00000496423	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1415450 Hom.: 0 Cov.: 29 AF XY: 0.00000143 AC XY: 1 AN XY: 699906

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.22e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cone-rod dystrophy and hearing loss 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Benign	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057517693; hg19: chr9-80855285;