20-63931020-G-A

Variant names:

• chr20-63931020-G-A
• rs762961919
• NM_025219.3:c.491G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_025219.3(DNAJC5):​c.491G>A​(p.Arg164Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000089 in 1,461,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: DNAJC5 NM_025219.3 missense, splice_region
• Scores: Splicing: ADA: 0.9573
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.75
• Publications: 1 publications found

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]

DNAJC5 Gene-Disease associations (from GenCC):

• ceroid lipofuscinosis, neuronal, 4 (Kufs type)

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• adult neuronal ceroid lipofuscinosis

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025219.3. 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
	DNAJC5	NM_025219.3	MANE Select	c.491G>A	p.Arg164Lys	missense splice_region	Exon 4 of 5	NP_079495.1	Q9H3Z4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJC5	ENST00000360864.9	TSL:1 MANE Select	c.491G>A	p.Arg164Lys	missense splice_region	Exon 4 of 5	ENSP00000354111.4	Q9H3Z4-1
	DNAJC5	ENST00000898575.1		c.491G>A	p.Arg164Lys	missense splice_region	Exon 4 of 5	ENSP00000568634.1
	DNAJC5	ENST00000898576.1		c.491G>A	p.Arg164Lys	missense splice_region	Exon 4 of 5	ENSP00000568635.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000280 AC: 7 AN: 249906 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461490 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727032

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111946

Other (OTH) AF: 0.0000331 AC: 2 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000404 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Neuronal ceroid lipofuscinosis (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.24
Sift	Benign	0.42	T
Sift4G	Benign	0.59	T
Polyphen		0.0050	B
Vest4		0.30
MVP		0.85
MPC		0.82
ClinPred		0.12	T
GERP RS		5.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.8
Varity_R		0.13
gMVP		0.59
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.76
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: rs762961919; hg19: chr20-62562373;