20-63895194-TGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCC

Variant names:

• chr20-63895194-T-TGCCGCC
• rs531246320
• NM_025219.3:c.-125_-120dupGCCGCC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_025219.3(DNAJC5):​c.-125_-120dupGCCGCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 153,706 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0031 (2 hom.)
• Consequence: DNAJC5 NM_025219.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75
• 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

ENSG00000290226 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 299 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.-125_-120dupGCCGCC		5_prime_UTR	Exon 1 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.-125_-120dupGCCGCC		5_prime_UTR	Exon 1 of 5	ENSP00000354111.4	Q9H3Z4-1
	DNAJC5	ENST00000898575.1		c.-120_-115dupGCCGCC		5_prime_UTR	Exon 1 of 5	ENSP00000568634.1
	DNAJC5	ENST00000921989.1		c.-37_-32dupGCCGCC		5_prime_UTR	Exon 1 of 5	ENSP00000592048.1

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 287 AN: 149082 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00419

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00180

Gnomad ASJ AF: 0.000293

Gnomad EAS AF: 0.000585

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000629

Gnomad OTH AF: 0.00194

GnomAD4 exome AF: 0.00310 AC: 14 AN: 4522 Hom.: 2 Cov.: 0 AF XY: 0.00250 AC XY: 8 AN XY: 3202

African (AFR) AF: 0.0333 AC: 2 AN: 60

American (AMR) AF: 0.00 AC: 0 AN: 40

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 36

East Asian (EAS) AF: 0.00 AC: 0 AN: 202

South Asian (SAS) AF: 0.00 AC: 0 AN: 900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 12

European-Non Finnish (NFE) AF: 0.00356 AC: 11 AN: 3092

Other (OTH) AF: 0.00685 AC: 1 AN: 146

GnomAD4 genome AF: 0.00200 AC: 299 AN: 149184 Hom.: 3 Cov.: 31 AF XY: 0.00224 AC XY: 163 AN XY: 72744

African (AFR) AF: 0.00447 AC: 184 AN: 41156

American (AMR) AF: 0.00180 AC: 27 AN: 15036

Ashkenazi Jewish (ASJ) AF: 0.000293 AC: 1 AN: 3412

East Asian (EAS) AF: 0.000587 AC: 3 AN: 5114

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4802

European-Finnish (FIN) AF: 0.00386 AC: 37 AN: 9594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000629 AC: 42 AN: 66792

Other (OTH) AF: 0.00192 AC: 4 AN: 2082

Alfa AF: 0.000123 Hom.: 12

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neuronal Ceroid-Lipofuscinosis, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.7
Mutation Taster		=298/2	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs531246320; hg19: chr20-62526547;