NM_018718.3:c.*4322G>A

Variant names:

• chr7-130394569-C-T
• rs538898722
• NM_018718.3:c.*4322G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. 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
• Publications: 0 publications found

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]

CEP41 Gene-Disease associations (from GenCC):

• Joubert syndrome 15

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with ocular defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018718.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP41	NM_018718.3	MANE Select	c.*4322G>A		3_prime_UTR	Exon 11 of 11	NP_061188.1	Q9BYV8-1
	CEP41	NM_001257158.2		c.*4322G>A		3_prime_UTR	Exon 10 of 10	NP_001244087.1	Q9BYV8-2
	CEP41	NM_001257159.2		c.*4322G>A		3_prime_UTR	Exon 9 of 9	NP_001244088.1	Q9BYV8-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP41	ENST00000223208.10	TSL:1 MANE Select	c.*4322G>A		3_prime_UTR	Exon 11 of 11	ENSP00000223208.4	Q9BYV8-1
	CEP41	ENST00000541543.6	TSL:2	c.*4322G>A		3_prime_UTR	Exon 11 of 11	ENSP00000445888.2	A0A7I2SYM4
	CEP41	ENST00000675649.1		c.*4322G>A		3_prime_UTR	Exon 9 of 9	ENSP00000502385.1	A0A6Q8PGR4

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

GnomAD2 exomes AF: 0.00249 AC: 319 AN: 127928 AF XY: 0.00241

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 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

African (AFR) AF: 0.000702 AC: 6 AN: 8552

American (AMR) AF: 0.00286 AC: 78 AN: 27272

Ashkenazi Jewish (ASJ) AF: 0.00427 AC: 46 AN: 10784

East Asian (EAS) AF: 0.00 AC: 0 AN: 9210

South Asian (SAS) AF: 0.00 AC: 0 AN: 59644

European-Finnish (FIN) AF: 0.00291 AC: 36 AN: 12364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1150

European-Non Finnish (NFE) AF: 0.00354 AC: 562 AN: 158756

Other (OTH) AF: 0.00278 AC: 39 AN: 14042

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

African (AFR) AF: 0.000938 AC: 39 AN: 41560

American (AMR) AF: 0.00353 AC: 54 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00409 AC: 278 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00337 Hom.: 0

Bravo AF: 0.00239

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Joubert syndrome 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.3
DANN	Benign	0.56
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism

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: rs538898722; hg19: chr7-130034410;