chr13-77001261-G-A

Variant names:

• chr13-77001261-G-A
• rs700363
• NM_006493.4:c.*292G>A

Variant summary

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

The NM_006493.4(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 NM_006493.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.60
• Publications: 13 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 -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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006493.4. 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
	CLN5	NM_006493.4	MANE Select	c.*292G>A		3_prime_UTR	Exon 4 of 4	NP_006484.2	O75503
	CLN5	NM_001366624.2		c.*818G>A		3_prime_UTR	Exon 5 of 5	NP_001353553.1	A0A1B0GTR6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN5	ENST00000377453.9	TSL:1 MANE Select	c.*292G>A		3_prime_UTR	Exon 4 of 4	ENSP00000366673.5	O75503
	CLN5	ENST00000636183.2	TSL:1	c.*292G>A		3_prime_UTR	Exon 4 of 4	ENSP00000490181.2	O75503
	ENSG00000283208	ENST00000638147.2	TSL:5	c.565+5134G>A		intron	N/A	ENSP00000490953.2	A0A1B0GWJ7

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

African (AFR) AF: 0.193 AC: 393 AN: 2034

American (AMR) AF: 0.176 AC: 596 AN: 3390

Ashkenazi Jewish (ASJ) AF: 0.0790 AC: 199 AN: 2518

East Asian (EAS) AF: 0.237 AC: 850 AN: 3580

South Asian (SAS) AF: 0.0743 AC: 557 AN: 7498

European-Finnish (FIN) AF: 0.0861 AC: 292 AN: 3392

Middle Eastern (MID) AF: 0.125 AC: 42 AN: 336

European-Non Finnish (NFE) AF: 0.0700 AC: 3592 AN: 51292

Other (OTH) AF: 0.0913 AC: 448 AN: 4906

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

African (AFR) AF: 0.207 AC: 8590 AN: 41456

American (AMR) AF: 0.162 AC: 2472 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0927 AC: 322 AN: 3472

East Asian (EAS) AF: 0.267 AC: 1379 AN: 5166

South Asian (SAS) AF: 0.0911 AC: 438 AN: 4810

European-Finnish (FIN) AF: 0.0921 AC: 976 AN: 10598

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.0737 AC: 5010 AN: 67992

Other (OTH) AF: 0.110 AC: 232 AN: 2112

Alfa AF: 0.0970 Hom.: 1682

Bravo AF: 0.139

Asia WGS AF: 0.189 AC: 657 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Neuronal ceroid lipofuscinosis 5 (1)
-	-	1	Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.013
DANN	Benign	0.43
PhyloP100		-3.6
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: rs700363; hg19: chr13-77575396;