chr13-77002892-T-C

Variant names:

• chr13-77002892-T-C
• rs9565309
• NM_006493.4:c.*1923T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006493.4(CLN5):​c.*1923T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0377 in 152,274 control chromosomes in the GnomAD database, including 217 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.038 (217 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: CLN5 NM_006493.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.498
• Publications: 9 publications found

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]

ENSG00000283208 (HGNC:):

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]

FBXL3 Gene-Disease associations (from GenCC):

• intellectual disability, short stature, facial anomalies, and joint dislocations

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN5	NM_006493.4	c.*1923T>C		3_prime_UTR_variant	Exon 4 of 4	ENST00000377453.9	NP_006484.2
CLN5	NM_001366624.2	c.*2449T>C		3_prime_UTR_variant	Exon 5 of 5		NP_001353553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN5	ENST00000377453.9	c.*1923T>C		3_prime_UTR_variant	Exon 4 of 4	1	NM_006493.4	ENSP00000366673.5
ENSG00000283208	ENST00000638147.2	c.565+6765T>C		intron_variant	Intron 3 of 4	5		ENSP00000490953.2

Frequencies

GnomAD3 genomes AF: 0.0377 AC: 5730 AN: 152156 Hom.: 218 Cov.: 32

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0982

Gnomad ASJ AF: 0.0253

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.0476

Gnomad FIN AF: 0.0384

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0329

Gnomad OTH AF: 0.0321

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0377 AC: 5738 AN: 152274 Hom.: 217 Cov.: 32 AF XY: 0.0401 AC XY: 2983 AN XY: 74466

African (AFR) AF: 0.0103 AC: 428 AN: 41566

American (AMR) AF: 0.0986 AC: 1508 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 88 AN: 3472

East Asian (EAS) AF: 0.138 AC: 717 AN: 5186

South Asian (SAS) AF: 0.0477 AC: 230 AN: 4824

European-Finnish (FIN) AF: 0.0384 AC: 407 AN: 10608

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0328 AC: 2234 AN: 68006

Other (OTH) AF: 0.0332 AC: 70 AN: 2108

Alfa AF: 0.0385 Hom.: 212

Bravo AF: 0.0421

Asia WGS AF: 0.0950 AC: 328 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.2
DANN	Benign	0.84
PhyloP100		0.50

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9565309; hg19: chr13-77577027;