3-132446505-T-A

Position:

• chr3-132446505-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2 PP2 BP4 BS2

The NM_015268.4(DNAJC13):​c.99T>A​(p.His33Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,457,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DNAJC13 NM_015268.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72

Genes affected

DNAJC13 (HGNC:30343): (DnaJ heat shock protein family (Hsp40) member C13) This gene encodes a member of the Dnaj protein family whose members act as co-chaperones of a partner heat-shock protein by binding to the latter and stimulating ATP hydrolysis. The encoded protein associates with the heat-shock protein Hsc70 and plays a role in clathrin-mediated endocytosis. It may also be involved in post-endocytic transport mechanisms via its associations with other proteins, including the sorting nexin SNX1. Mutations in this gene are associated with Parkinson's disease. [provided by RefSeq, Jun 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNAJC13. . Gene score misZ 2.2836 (greater than the threshold 3.09). Trascript score misZ 3.3776 (greater than threshold 3.09). GenCC has associacion of gene with hereditary late onset Parkinson disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3382023).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJC13	NM_015268.4	c.99T>A	p.His33Gln	missense_variant	3/56	ENST00000260818.11	NP_056083.3
DNAJC13	NM_001329126.2	c.99T>A	p.His33Gln	missense_variant	3/57		NP_001316055.1
DNAJC13	XM_047447819.1	c.99T>A	p.His33Gln	missense_variant	3/57		XP_047303775.1
DNAJC13	XM_047447820.1	c.99T>A	p.His33Gln	missense_variant	3/56		XP_047303776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJC13	ENST00000260818.11	c.99T>A	p.His33Gln	missense_variant	3/56	1	NM_015268.4	ENSP00000260818	P1
DNAJC13	ENST00000486798.5	n.164T>A		non_coding_transcript_exon_variant	3/20	1
DNAJC13	ENST00000650455.1	c.99T>A	p.His33Gln	missense_variant, NMD_transcript_variant	3/57			ENSP00000496825

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1457262 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 724942

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Dec 01, 2022

The c.99T>A (p.H33Q) alteration is located in exon 3 (coding exon 2) of the DNAJC13 gene. This alteration results from a T to A substitution at nucleotide position 99, causing the histidine (H) at amino acid position 33 to be replaced by a glutamine (Q). 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	Benign	0.16
BayesDel_addAF	Benign	0.0065	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Benign	0.76
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.023
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.093
Sift	Benign	0.63	T
Sift4G	Benign	0.41	T
Polyphen		0.48	P
Vest4		0.70
MutPred		0.36		Loss of glycosylation at T36 (P = 0.0346);
MVP		0.45
MPC		0.24
ClinPred		0.58	D
GERP RS		5.5
Varity_R		0.14
gMVP		0.51

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: rs1933248402; hg19: chr3-132165349;