rs587776892

chr20-63930870-GCCT-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM4_Supporting PP5_Very_Strong

The NM_025219.3(DNAJC5):c.346_348del(p.Leu116del) variant causes a inframe deletion change. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G114G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAJC5 NM_025219.3 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.47

Genes affected

DNAJC5 (HGNC:16235): (DnaJ heat shock protein family (Hsp40) member C5) This gene is a member of the J protein family. J proteins function in many cellular processes by regulating the ATPase activity of 70 kDa heat shock proteins. The encoded protein plays a role in membrane trafficking and protein folding, and has been shown to have anti-neurodegenerative properties. The encoded protein is known to play a role in cystic fibrosis and Huntington's disease. A pseudogene of this gene is located on the short arm of chromosome 8. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_025219.3
• PM4: Nonframeshift variant in NON repetitive region in NM_025219.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 20-63930870-GCCT-G is Pathogenic according to our data. Variant chr20-63930870-GCCT-G is described in ClinVar as [Pathogenic]. Clinvar id is 30893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63930870-GCCT-G is described in Lovd as [Pathogenic]. Variant chr20-63930870-GCCT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJC5	NM_025219.3	c.346_348del	p.Leu116del	inframe_deletion	4/5	ENST00000360864.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJC5	ENST00000360864.9	c.346_348del	p.Leu116del	inframe_deletion	4/5	1	NM_025219.3	P1
DNAJC5	ENST00000470551.1	c.346_348del	p.Leu116del	inframe_deletion, NMD_transcript_variant	4/6	2
DNAJC5	ENST00000703637.1	c.346_348del	p.Leu116del	inframe_deletion, NMD_transcript_variant	4/6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1460954 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726762

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ceroid lipofuscinosis, neuronal, 4 (Kufs type) Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Research Unit for Rare Diseases, 1st Faculty of Medicine, Charles University in Prague	Sep 01, 2019	The c.343_345del (p.(L116del)), in exon 4 of DNAJC5 (NM_025219.2) variant was reported by Noskova et al. in 2011 as causative for autosomal dominant adult-onset neuronal ceroid lipofuscinosis (DOI: 10.1016/j.ajhg.2011.07.003). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2013	- -

Neuronal ceroid lipofuscinosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 19, 2023

This variant, c.346_348del, results in the deletion of 1 amino acid(s) of the DNAJC5 protein (p.Leu116del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with adult-onset neuronal ceroid lipofuscinosis (PMID: 21820099, 22073189, 22235333, 22978711). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30893). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects DNAJC5 function (PMID: 21820099, 22902780). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs587776892; hg19: chr20-62562223;