20-63930873-T-G

Position:

• chr20-63930873-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_025219.3(DNAJC5):​c.344T>G​(p.Leu115Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAJC5 NM_025219.3 missense
• 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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879
• PP5: Variant 20-63930873-T-G is Pathogenic according to our data. Variant chr20-63930873-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 30894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63930873-T-G is described in Lovd as [Pathogenic]. Variant chr20-63930873-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJC5	NM_025219.3	c.344T>G	p.Leu115Arg	missense_variant	4/5	ENST00000360864.9	NP_079495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJC5	ENST00000360864.9	c.344T>G	p.Leu115Arg	missense_variant	4/5	1	NM_025219.3	ENSP00000354111.4
DNAJC5	ENST00000470551.1	n.344T>G		non_coding_transcript_exon_variant	4/6	2		ENSP00000434744.1
DNAJC5	ENST00000703637.1	n.344T>G		non_coding_transcript_exon_variant	4/6			ENSP00000515413.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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	-	The c.344T>G (p.(L115R)) in exon 4 of DNAJC5 (NM_025219.2) variant was reported by Noskova et al. in 2011 as causative for ausomal 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	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 08, 2022

Published functional studies demonstrate a damaging effect on protein function (Greaves et al., 2012; Jedlikov et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22978711, 26610600, 31919451, 24277206, 22235333, 21820099, 12112194, 11489285, 22073189, 22902780) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.028	D
Polyphen		0.069	B
Vest4		0.96
MutPred		0.63		Gain of solvent accessibility (P = 0.0039);
MVP		0.93
MPC		1.2
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.83
gMVP		0.95

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: rs387907043; hg19: chr20-62562226;