NM_006493.4:c.381T>G

Variant names:

• chr13-76995943-T-G
• rs34481987
• NM_006493.4:c.381T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006493.4(CLN5):​c.381T>G​(p.Thr127Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,614,110 control chromosomes in the GnomAD database, including 452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T127T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (34 hom., cov: 33)
  • Exomes 𝑓: 0.019 (418 hom.)
• Consequence: CLN5 NM_006493.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.284
• Publications: 8 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 13-76995943-T-G is Benign according to our data. Variant chr13-76995943-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.284 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0644 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.381T>G	p.Thr127Thr	synonymous	Exon 3 of 4	NP_006484.2	O75503
	CLN5	NM_001366624.2		c.381T>G	p.Thr127Thr	synonymous	Exon 3 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.381T>G	p.Thr127Thr	synonymous	Exon 3 of 4	ENSP00000366673.5	O75503
	CLN5	ENST00000636183.2	TSL:1	c.381T>G	p.Thr127Thr	synonymous	Exon 3 of 4	ENSP00000490181.2	O75503
	ENSG00000283208	ENST00000638147.2	TSL:5	c.381T>G	p.Thr127Thr	synonymous	Exon 3 of 5	ENSP00000490953.2	A0A1B0GWJ7

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2310 AN: 152200 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.00398

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0241

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.0702

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.00555

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0164

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0202 AC: 5081 AN: 251484 AF XY: 0.0200

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.0274

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.0657

Gnomad FIN exome AF: 0.00651

Gnomad NFE exome AF: 0.0178

Gnomad OTH exome AF: 0.0186

GnomAD4 exome AF: 0.0190 AC: 27741 AN: 1461792 Hom.: 418 Cov.: 31 AF XY: 0.0186 AC XY: 13546 AN XY: 727210

African (AFR) AF: 0.00346 AC: 116 AN: 33480

American (AMR) AF: 0.0272 AC: 1216 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 347 AN: 26136

East Asian (EAS) AF: 0.0858 AC: 3408 AN: 39698

South Asian (SAS) AF: 0.0158 AC: 1360 AN: 86252

European-Finnish (FIN) AF: 0.00779 AC: 416 AN: 53420

Middle Eastern (MID) AF: 0.0253 AC: 146 AN: 5768

European-Non Finnish (NFE) AF: 0.0176 AC: 19552 AN: 1111924

Other (OTH) AF: 0.0195 AC: 1180 AN: 60390

GnomAD4 genome AF: 0.0152 AC: 2310 AN: 152318 Hom.: 34 Cov.: 33 AF XY: 0.0151 AC XY: 1128 AN XY: 74496

African (AFR) AF: 0.00397 AC: 165 AN: 41586

American (AMR) AF: 0.0241 AC: 369 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3472

East Asian (EAS) AF: 0.0704 AC: 364 AN: 5170

South Asian (SAS) AF: 0.0180 AC: 87 AN: 4826

European-Finnish (FIN) AF: 0.00555 AC: 59 AN: 10626

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0164 AC: 1117 AN: 68030

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.0176 Hom.: 70

Bravo AF: 0.0176

Asia WGS AF: 0.0390 AC: 135 AN: 3478

EpiCase AF: 0.0179

EpiControl AF: 0.0193

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Neuronal ceroid lipofuscinosis 5 (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neuronal ceroid lipofuscinosis (1)
-	-	1	Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.7
DANN	Benign	0.74
PhyloP100		-0.28
PromoterAI		-0.0078	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34481987; hg19: chr13-77570078; COSMIC: COSV66284714; COSMIC: COSV66284714;