Genetic Variant NM_001330691.3:c.1A>G (chr9-78236351-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_001330691.3(CEP78):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000211 in 1,418,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CEP78
NM_001330691.3 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.36

Variant links:

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]

CEP78 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 88 codons. Genomic position: 78240031. Lost 0.124 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP78	NM_001330691.3 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 17	ENST00000643273.2	NP_001317620.1	Q5JTW2-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP78	ENST00000643273.2 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 17		NM_001330691.3	ENSP00000496423.2		Q5JTW2-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000559

AC:

AN:

178920

Hom.:

AF XY:

0.00

AC XY:

AN XY:

99108

show subpopulations

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 SAS exome

AF:

0.0000391

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000211

AC:

AN:

1418920

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

703194

show subpopulations

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:

0.0000122

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000183

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000846

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.053

T;.;.;.;.;.;.;.;.;T;.;.;.;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

D;D;D;D;D;D;D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.56

PROVEAN

Benign

-1.4

N;.;.;.;.;.;.;N;N;N;.;.;.;N

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

D;.;.;.;.;.;.;D;D;D;.;.;.;D

Sift4G

Pathogenic

0.0

D;.;.;.;.;.;.;D;D;D;.;.;.;D

Polyphen

1.0

D;.;.;.;.;.;.;.;P;.;.;.;.;.

Vest4

0.53

MutPred

0.99

Loss of ubiquitination at K6 (P = 0.0935);Loss of ubiquitination at K6 (P = 0.0935);Loss of ubiquitination at K6 (P = 0.0935);Loss of ubiquitination at K6 (P = 0.0935);Loss of ubiquitination at K6 (P = 0.0935);Loss of ubiquitination at K6 (P = 0.0935);Loss of ubiquitination at K6 (P = 0.0935);Loss of ubiquitination at K6 (P = 0.0935);Loss of ubiquitination at K6 (P = 0.0935);Loss of ubiquitination at K6 (P = 0.0935);Loss of ubiquitination at K6 (P = 0.0935);Loss of ubiquitination at K6 (P = 0.0935);Loss of ubiquitination at K6 (P = 0.0935);Loss of ubiquitination at K6 (P = 0.0935);

MVP

0.73

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.62

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over