rs12625454

Variant names:

• chr20-63919928-C-G
• rs12625454
• NM_025219.3:c.-11-8407C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_025219.3(DNAJC5):​c.-11-8407C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 3)
  • Exomes 𝑓: 0.0040 (16 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAJC5 NM_025219.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.988
• Publications: 5 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]

LOC124904951 (HGNC:):

MIR941-5 (HGNC:50845): (microRNA 941-5) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR941-4 (HGNC:33687): (microRNA 941-4) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC5	NM_025219.3	c.-11-8407C>G		intron_variant	Intron 1 of 4	ENST00000360864.9	NP_079495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJC5	ENST00000360864.9	c.-11-8407C>G		intron_variant	Intron 1 of 4	1	NM_025219.3	ENSP00000354111.4

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 33 AN: 19166 Hom.: 0 Cov.: 3

Gnomad AFR AF: 0.000851

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

Gnomad ASJ AF: 0.00110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000290 AC: 47 AN: 161882 AF XY: 0.000185

Gnomad AFR exome AF: 0.000121

Gnomad AMR exome AF: 0.000431

Gnomad ASJ exome AF: 0.000117

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000446

Gnomad NFE exome AF: 0.000321

Gnomad OTH exome AF: 0.000903

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00403 AC: 931 AN: 230804 Hom.: 16 Cov.: 0 AF XY: 0.00320 AC XY: 431 AN XY: 134794

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000601 AC: 3 AN: 4990

American (AMR) AF: 0.00169 AC: 25 AN: 14778

Ashkenazi Jewish (ASJ) AF: 0.00199 AC: 17 AN: 8526

East Asian (EAS) AF: 0.00 AC: 0 AN: 3244

South Asian (SAS) AF: 0.000968 AC: 49 AN: 50614

European-Finnish (FIN) AF: 0.0155 AC: 134 AN: 8644

Middle Eastern (MID) AF: 0.00207 AC: 2 AN: 966

European-Non Finnish (NFE) AF: 0.00515 AC: 661 AN: 128408

Other (OTH) AF: 0.00376 AC: 40 AN: 10634

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00172 AC: 33 AN: 19168 Hom.: 0 Cov.: 3 AF XY: 0.00216 AC XY: 20 AN XY: 9238

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000848 AC: 2 AN: 2358

American (AMR) AF: 0.00111 AC: 2 AN: 1798

Ashkenazi Jewish (ASJ) AF: 0.00110 AC: 1 AN: 906

East Asian (EAS) AF: 0.00 AC: 0 AN: 204

South Asian (SAS) AF: 0.00 AC: 0 AN: 658

European-Finnish (FIN) AF: 0.0102 AC: 9 AN: 886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 52

European-Non Finnish (NFE) AF: 0.00159 AC: 19 AN: 11958

Other (OTH) AF: 0.00 AC: 0 AN: 284

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0199 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	4.9
DANN	Benign	0.53
PhyloP100		-0.99

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

Other links and lift over

dbSNP: rs12625454; hg19: chr20-62551281; COSMIC: COSV62670891; COSMIC: COSV62670891;