rs78457562

Variant names:

• chr20-63930841-C-T
• rs78457562
• NM_025219.3:c.322-10C>T

Variant summary

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

The NM_025219.3(DNAJC5):​c.322-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0725 in 1,612,042 control chromosomes in the GnomAD database, including 4,963 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (532 hom., cov: 33)
  • Exomes 𝑓: 0.072 (4431 hom.)
• Consequence: DNAJC5 NM_025219.3 intron
• Scores: Splicing: ADA: 0.00001350
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.529
• Publications: 3 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• adult neuronal ceroid lipofuscinosis

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 20-63930841-C-T is Benign according to our data. Variant chr20-63930841-C-T is described in ClinVar as Benign. ClinVar VariationId is 137124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

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.322-10C>T		intron	N/A	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.322-10C>T		intron	N/A	ENSP00000354111.4	Q9H3Z4-1
	DNAJC5	ENST00000898575.1		c.322-10C>T		intron	N/A	ENSP00000568634.1
	DNAJC5	ENST00000898576.1		c.322-10C>T		intron	N/A	ENSP00000568635.1

Frequencies

GnomAD3 genomes AF: 0.0744 AC: 11319 AN: 152200 Hom.: 528 Cov.: 33

Gnomad AFR AF: 0.0680

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0472

Gnomad ASJ AF: 0.0464

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.0343

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0792

Gnomad OTH AF: 0.0651

GnomAD2 exomes AF: 0.0654 AC: 16368 AN: 250390 AF XY: 0.0641

Gnomad AFR exome AF: 0.0668

Gnomad AMR exome AF: 0.0315

Gnomad ASJ exome AF: 0.0432

Gnomad EAS exome AF: 0.00180

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.0731

Gnomad OTH exome AF: 0.0673

GnomAD4 exome AF: 0.0723 AC: 105498 AN: 1459724 Hom.: 4431 Cov.: 32 AF XY: 0.0714 AC XY: 51875 AN XY: 726160

African (AFR) AF: 0.0705 AC: 2355 AN: 33422

American (AMR) AF: 0.0320 AC: 1432 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0445 AC: 1162 AN: 26128

East Asian (EAS) AF: 0.00242 AC: 96 AN: 39700

South Asian (SAS) AF: 0.0408 AC: 3513 AN: 86180

European-Finnish (FIN) AF: 0.175 AC: 9251 AN: 52920

Middle Eastern (MID) AF: 0.0294 AC: 135 AN: 4586

European-Non Finnish (NFE) AF: 0.0751 AC: 83451 AN: 1111836

Other (OTH) AF: 0.0681 AC: 4103 AN: 60238

GnomAD4 genome AF: 0.0745 AC: 11344 AN: 152318 Hom.: 532 Cov.: 33 AF XY: 0.0775 AC XY: 5770 AN XY: 74478

African (AFR) AF: 0.0685 AC: 2850 AN: 41576

American (AMR) AF: 0.0470 AC: 719 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 161 AN: 3472

East Asian (EAS) AF: 0.00328 AC: 17 AN: 5190

South Asian (SAS) AF: 0.0340 AC: 164 AN: 4830

European-Finnish (FIN) AF: 0.175 AC: 1851 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0792 AC: 5387 AN: 68026

Other (OTH) AF: 0.0653 AC: 138 AN: 2112

Alfa AF: 0.0749 Hom.: 137

Bravo AF: 0.0635

Asia WGS AF: 0.0370 AC: 129 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Ceroid lipofuscinosis, neuronal, 4 (Kufs type) (1)
-	-	1	Neuronal ceroid lipofuscinosis (1)
-	-	1	Neuronal Ceroid-Lipofuscinosis, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.63
DANN	Benign	0.56
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0
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: rs78457562; hg19: chr20-62562194;