1-3815093-C-T

Variant names:

• chr1-3815093-C-T
• rs34060840
• NM_014704.4:c.*309G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014704.4(CEP104):​c.*309G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 344,524 control chromosomes in the GnomAD database, including 3,674 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2196 hom., cov: 34)
  • Exomes 𝑓: 0.11 (1478 hom.)
• Consequence: CEP104 NM_014704.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.195
• Publications: 7 publications found

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]

CEP104 Gene-Disease associations (from GenCC):

• Joubert syndrome 25

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-3815093-C-T is Benign according to our data. Variant chr1-3815093-C-T is described in ClinVar as [Benign]. Clinvar id is 1231645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP104	NM_014704.4	c.*309G>A		3_prime_UTR_variant	Exon 22 of 22	ENST00000378230.8	NP_055519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP104	ENST00000378230.8	c.*309G>A		3_prime_UTR_variant	Exon 22 of 22	5	NM_014704.4	ENSP00000367476.3

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24198 AN: 151822 Hom.: 2195 Cov.: 34

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.0472

Gnomad SAS AF: 0.0944

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.145

GnomAD4 exome AF: 0.114 AC: 21963 AN: 192584 Hom.: 1478 Cov.: 0 AF XY: 0.113 AC XY: 11413 AN XY: 101384

African (AFR) AF: 0.242 AC: 1145 AN: 4740

American (AMR) AF: 0.0845 AC: 577 AN: 6828

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 1187 AN: 6166

East Asian (EAS) AF: 0.0506 AC: 534 AN: 10556

South Asian (SAS) AF: 0.0810 AC: 1769 AN: 21846

European-Finnish (FIN) AF: 0.138 AC: 1612 AN: 11662

Middle Eastern (MID) AF: 0.112 AC: 99 AN: 882

European-Non Finnish (NFE) AF: 0.114 AC: 13496 AN: 118386

Other (OTH) AF: 0.134 AC: 1544 AN: 11518

GnomAD4 genome AF: 0.159 AC: 24229 AN: 151940 Hom.: 2196 Cov.: 34 AF XY: 0.157 AC XY: 11697 AN XY: 74268

African (AFR) AF: 0.244 AC: 10085 AN: 41370

American (AMR) AF: 0.107 AC: 1633 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 678 AN: 3470

East Asian (EAS) AF: 0.0477 AC: 246 AN: 5154

South Asian (SAS) AF: 0.0949 AC: 457 AN: 4814

European-Finnish (FIN) AF: 0.158 AC: 1667 AN: 10576

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 8999 AN: 67962

Other (OTH) AF: 0.146 AC: 308 AN: 2112

Alfa AF: 0.147 Hom.: 402

Bravo AF: 0.161

Asia WGS AF: 0.0780 AC: 275 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.65
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34060840; hg19: chr1-3731657;