1-3815444-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_014704.4(CEP104):c.2736C>T(p.Gly912=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,613,194 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0017 (4 hom.)
• Consequence: CEP104 NM_014704.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.850

Genes affected

CEP104 (HGNC:24866): (centrosomal protein 104) This gene encodes a centrosomal protein required for ciliogenesis and for ciliary tip structural integrity. The mammalian protein contains three amino-terminal hydrophobic domains, two glycosylation sites, four cysteine-rich motifs, and two regions with homology to the glutamate receptor ionotropic, NMDA 1 protein. During ciliogenesis, the encoded protein translocates from the distal tips of the centrioles to the tip of the elongating cilium. Knockdown of the protein in human retinal pigment cells results in severe defects in ciliogenesis with structural deformities at the ciliary tips. Allelic variants of this gene are associated with the autosomal-recessive disorder Joubert syndrome, which is characterized by a distinctive mid-hindbrain and cerebellar malformation, oculomotor apraxia, irregular breathing, developmental delay, and ataxia. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 1-3815444-G-A is Benign according to our data. Variant chr1-3815444-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 707534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-3815444-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.85 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00116 (176/152362) while in subpopulation NFE AF= 0.0019 (129/68028). AF 95% confidence interval is 0.00163. There are 1 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP104	NM_014704.4	c.2736C>T	p.Gly912=	synonymous_variant	22/22	ENST00000378230.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP104	ENST00000378230.8	c.2736C>T	p.Gly912=	synonymous_variant	22/22	5	NM_014704.4	P4

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152244 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000530

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00106 AC: 265 AN: 249502 Hom.: 1 AF XY: 0.00102 AC XY: 138 AN XY: 135000

Gnomad AFR exome AF: 0.000497

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000599

Gnomad SAS exome AF: 0.00145

Gnomad FIN exome AF: 0.000236

Gnomad NFE exome AF: 0.00152

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00171 AC: 2496 AN: 1460832 Hom.: 4 Cov.: 31 AF XY: 0.00171 AC XY: 1242 AN XY: 726670

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.000560

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.00138

Gnomad4 FIN exome AF: 0.000113

Gnomad4 NFE exome AF: 0.00198

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152362 Hom.: 1 Cov.: 34 AF XY: 0.000993 AC XY: 74 AN XY: 74508

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.00117

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00225

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2020	- -

Joubert syndrome 25 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	2.5
Dann	Benign	0.47

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: rs148360595; hg19: chr1-3732008;