chr20-63895322-AGGTGAGCTCGCTGCGGGTCGGGCGGGCG-A

Position:

• chr20-63895322-AGGTGAGCTCGCTGCGGGTCGGGCGGGCG-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_Strong BS2

The NM_025219.3(DNAJC5):​c.-12+1_-12+28del variant causes a splice donor, splice donor 5th base, 5 prime UTR, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 144,326 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.00010 (0 hom., cov: 32)
• Consequence: DNAJC5 NM_025219.3 splice_donor, splice_donor_5th_base, 5_prime_UTR, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57

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 Uncertain_significance. Variant got 0 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.32998326 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.7, offset of 43, new splice context is: cggGTgggg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BS2: High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJC5	NM_025219.3	c.-12+1_-12+28del		splice_donor_variant, splice_donor_5th_base_variant, 5_prime_UTR_variant, intron_variant	1/5	ENST00000360864.9	NP_079495.1
DNAJC5	XM_047440509.1	c.-1696_-1669del		5_prime_UTR_variant	1/5		XP_047296465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJC5	ENST00000360864.9	c.-12+1_-12+28del		splice_donor_variant, splice_donor_5th_base_variant, 5_prime_UTR_variant, intron_variant	1/5	1	NM_025219.3	ENSP00000354111	P1
DNAJC5	ENST00000470551.1	c.-12+1_-12+28del		splice_donor_variant, splice_donor_5th_base_variant, 5_prime_UTR_variant, intron_variant, NMD_transcript_variant	1/6	2		ENSP00000434744

Frequencies

GnomAD3 genomes AF: 0.000104 AC: 15 AN: 144326 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000497

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000200

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.000104 AC: 15 AN: 144326 Hom.: 0 Cov.: 32 AF XY: 0.0000713 AC XY: 5 AN XY: 70144

Gnomad4 AFR AF: 0.0000497

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000200

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.0000945

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 14, 2023

In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge; No data available from control populations to assess the frequency of this variant -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1306801393; hg19: chr20-62526675;