7-130394569-C-T

Position:

• chr7-130394569-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_018718.3(CEP41):​c.*4322G>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 0.0026 in 454,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (0 hom.)
• Consequence: CEP41 NM_018718.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.129

Genes affected

CEP41 (HGNC:12370): (centrosomal protein 41) This gene encodes a centrosomal and microtubule-binding protein which is predicted to have two coiled-coil domains and a rhodanese domain. In human retinal pigment epithelial cells the protein localized to centrioles and cilia. Mutations in this gene have been associated with Joubert Syndrome 15; an autosomal recessive ciliopathy and neurological disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00271 (413/152290) while in subpopulation NFE AF= 0.00409 (278/68024). AF 95% confidence interval is 0.00369. There are 0 homozygotes in gnomad4. There are 176 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP41	NM_018718.3	c.*4322G>A		3_prime_UTR_variant	11/11	ENST00000223208.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP41	ENST00000223208.10	c.*4322G>A		3_prime_UTR_variant	11/11	1	NM_018718.3	P3
CEP41	ENST00000541543.6	c.*4322G>A		3_prime_UTR_variant	11/11	2
CEP41	ENST00000675649.1	c.*4322G>A		3_prime_UTR_variant	9/9

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 413 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00409

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00249 AC: 319 AN: 127928 Hom.: 0 AF XY: 0.00241 AC XY: 169 AN XY: 70068

Gnomad AFR exome AF: 0.000821

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.00334

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00223

Gnomad NFE exome AF: 0.00385

Gnomad OTH exome AF: 0.00553

GnomAD4 exome AF: 0.00254 AC: 767 AN: 301774 Hom.: 0 Cov.: 0 AF XY: 0.00227 AC XY: 391 AN XY: 171984

Gnomad4 AFR exome AF: 0.000702

Gnomad4 AMR exome AF: 0.00286

Gnomad4 ASJ exome AF: 0.00427

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00291

Gnomad4 NFE exome AF: 0.00354

Gnomad4 OTH exome AF: 0.00278

GnomAD4 genome AF: 0.00271 AC: 413 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.00236 AC XY: 176 AN XY: 74452

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00409

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00337 Hom.: 0

Bravo AF: 0.00239

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome 15 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.3
DANN	Benign	0.56

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: rs538898722; hg19: chr7-130034410;