9-111653175-T-C

Position:

• chr9-111653175-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001015882.3(DNAJC25):​c.1036T>C​(p.Trp346Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000689 in 1,450,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: DNAJC25 NM_001015882.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

DNAJC25 (HGNC:34187): (DnaJ heat shock protein family (Hsp40) member C25) Predicted to be involved in protein folding. Predicted to be located in membrane. Predicted to be integral component of membrane. Predicted to be active in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

DNAJC25-GNG10 (HGNC:37501): (DNAJC25-GNG10 readthrough) This gene represents naturally-occurring mRNAs that are co-transcribed products of the neighboring DNAJC25 and GNG10 genes. These transcripts include the first exon of DNAJC25 and the last two exons of GNG10, resulting in a protein that combines the N-terminus of DNAJC25 and the C-terminus of GNG10. [provided by RefSeq, Dec 2008]

DNAJC25 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJC25	NM_001015882.3	c.1036T>C	p.Trp346Arg	missense_variant	4/4	ENST00000313525.4	NP_001015882.2
DNAJC25-GNG10	NM_004125.4	c.337-13640T>C		intron_variant			NP_004116.2
DNAJC25	NR_037148.2	n.1348T>C		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJC25	ENST00000313525.4	c.1036T>C	p.Trp346Arg	missense_variant	4/4	1	NM_001015882.3	ENSP00000320650.3
DNAJC25-GNG10	ENST00000374294.3	c.337-13640T>C		intron_variant		2		ENSP00000363412.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000689 AC: 10 AN: 1450558 Hom.: 0 Cov.: 30 AF XY: 0.00000831 AC XY: 6 AN XY: 721782

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000905

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2024

The c.1036T>C (p.W346R) alteration is located in exon 4 (coding exon 4) of the DNAJC25 gene. This alteration results from a T to C substitution at nucleotide position 1036, causing the tryptophan (W) at amino acid position 346 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.57		Gain of disorder (P = 9e-04);
MVP		0.63
MPC		0.83
ClinPred		1.0	D
GERP RS		6.2
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.92
gMVP		0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs780384327; hg19: chr9-114415455;