rs700363

Positions:

• chr13-77001261-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000377453.9(CLN5):​c.*292G>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 0.115 in 231,036 control chromosomes in the GnomAD database, including 2,055 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1625 hom., cov: 32)
  • Exomes 𝑓: 0.088 (430 hom.)
• Consequence: CLN5 ENST00000377453.9 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.60

Genes affected

CLN5 (HGNC:2076): (CLN5 intracellular trafficking protein) This gene is one of eight which have been associated with neuronal ceroid lipofuscinoses (NCL). Also referred to as Batten disease, NCL comprises a class of autosomal recessive, neurodegenerative disorders affecting children. The genes responsible likely encode proteins involved in the degradation of post-translationally modified proteins in lysosomes. The primary defect in NCL disorders is thought to be associated with lysosomal storage function.[provided by RefSeq, Oct 2008]

FBXL3 (HGNC:13599): (F-box and leucine rich repeat protein 3) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains several tandem leucine-rich repeats and is localized in the nucleus. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 13-77001261-G-A is Benign according to our data. Variant chr13-77001261-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 312434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN5	NM_006493.4	c.*292G>A		3_prime_UTR_variant	4/4	ENST00000377453.9	NP_006484.2
CLN5	NM_001366624.2	c.*818G>A		3_prime_UTR_variant	5/5		NP_001353553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN5	ENST00000377453.9	c.*292G>A		3_prime_UTR_variant	4/4	1	NM_006493.4	ENSP00000366673	P1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19536 AN: 151972 Hom.: 1623 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.0927

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.0916

Gnomad FIN AF: 0.0921

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.0737

Gnomad OTH AF: 0.110

GnomAD4 exome AF: 0.0883 AC: 6969 AN: 78946 Hom.: 430 Cov.: 0 AF XY: 0.0861 AC XY: 3526 AN XY: 40970

Gnomad4 AFR exome AF: 0.193

Gnomad4 AMR exome AF: 0.176

Gnomad4 ASJ exome AF: 0.0790

Gnomad4 EAS exome AF: 0.237

Gnomad4 SAS exome AF: 0.0743

Gnomad4 FIN exome AF: 0.0861

Gnomad4 NFE exome AF: 0.0700

Gnomad4 OTH exome AF: 0.0913

GnomAD4 genome AF: 0.129 AC: 19573 AN: 152090 Hom.: 1625 Cov.: 32 AF XY: 0.132 AC XY: 9813 AN XY: 74342

Gnomad4 AFR AF: 0.207

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.0927

Gnomad4 EAS AF: 0.267

Gnomad4 SAS AF: 0.0911

Gnomad4 FIN AF: 0.0921

Gnomad4 NFE AF: 0.0737

Gnomad4 OTH AF: 0.110

Alfa AF: 0.0895 Hom.: 1007

Bravo AF: 0.139

Asia WGS AF: 0.189 AC: 657 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Neuronal ceroid lipofuscinosis 5 Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.013
DANN	Benign	0.43

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: rs700363; hg19: chr13-77575396;