NM_001330691.3:c.1A>T

Variant names:

• chr9-78236351-A-T
• rs761538280
• NM_001330691.3:c.1A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001330691.3(CEP78):​c.1A>T​(p.Met1?) variant causes a initiator codon change. The variant allele was found at a frequency of 0.000000705 in 1,418,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CEP78 NM_001330691.3 initiator_codon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.36

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 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	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 17	ENST00000643273.2	NP_001317620.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1418920 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 703194

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: 9.13e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the CEP78 mRNA. The next in-frame methionine is located at codon 88. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CEP78-related conditions. ClinVar contains an entry for this variant (Variation ID: 2018416). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Benign	0.94
DEOGEN2	Benign	0.14	T;.;.;.;.;.;.;.;.;T;.;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.66	T
PROVEAN	Benign	-1.2	N;.;.;.;.;.;.;N;N;N;.;.;.;N
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;D;D;D;.;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;.;.;.;.;D;D;D;.;.;.;D
Polyphen		0.99	D;.;.;.;.;.;.;.;P;.;.;.;.;.
Vest4		0.72
MutPred		0.99		Loss of ubiquitination at K6 (P = 0.1083);Loss of ubiquitination at K6 (P = 0.1083);Loss of ubiquitination at K6 (P = 0.1083);Loss of ubiquitination at K6 (P = 0.1083);Loss of ubiquitination at K6 (P = 0.1083);Loss of ubiquitination at K6 (P = 0.1083);Loss of ubiquitination at K6 (P = 0.1083);Loss of ubiquitination at K6 (P = 0.1083);Loss of ubiquitination at K6 (P = 0.1083);Loss of ubiquitination at K6 (P = 0.1083);Loss of ubiquitination at K6 (P = 0.1083);Loss of ubiquitination at K6 (P = 0.1083);Loss of ubiquitination at K6 (P = 0.1083);Loss of ubiquitination at K6 (P = 0.1083);
MVP		0.61
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.96
gMVP		0.55

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

Other links and lift over

dbSNP: rs761538280; hg19: chr9-80851267;