3-132446504-A-G

Variant names:

• chr3-132446504-A-G
• rs1933248311
• NM_015268.4:c.98A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_015268.4(DNAJC13):​c.98A>G​(p.His33Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000808 in 1,609,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H33Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: DNAJC13 NM_015268.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.31
• Publications: 0 publications found

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]

DNAJC13 Gene-Disease associations (from GenCC):

• hereditary late onset Parkinson disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36975193).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015268.4. 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
	DNAJC13	NM_015268.4	MANE Select	c.98A>G	p.His33Arg	missense	Exon 3 of 56	NP_056083.3	O75165
	DNAJC13	NM_001329126.2		c.98A>G	p.His33Arg	missense	Exon 3 of 57	NP_001316055.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJC13	ENST00000260818.11	TSL:1 MANE Select	c.98A>G	p.His33Arg	missense	Exon 3 of 56	ENSP00000260818.6	O75165
	DNAJC13	ENST00000486798.5	TSL:1	n.163A>G		non_coding_transcript_exon	Exon 3 of 20
	DNAJC13	ENST00000650455.1		n.98A>G		non_coding_transcript_exon	Exon 3 of 57	ENSP00000496825.1	A0A3B3IRM0

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000824 AC: 12 AN: 1457074 Hom.: 0 Cov.: 29 AF XY: 0.00000552 AC XY: 4 AN XY: 724850

African (AFR) AF: 0.0000301 AC: 1 AN: 33258

American (AMR) AF: 0.00 AC: 0 AN: 43596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39416

South Asian (SAS) AF: 0.00 AC: 0 AN: 85218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000991 AC: 11 AN: 1110300

Other (OTH) AF: 0.00 AC: 0 AN: 60208

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74262

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67954

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000417 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	DNAJC13-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.064
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		7.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.030	N
REVEL	Benign	0.18
Sift	Benign	0.64	T
Sift4G	Benign	0.45	T
Polyphen		0.16	B
Vest4		0.67
MutPred		0.49		Gain of MoRF binding (P = 0.0165)
MVP		0.47
MPC		0.29
ClinPred		0.84	D
GERP RS		5.5
Varity_R		0.18
gMVP		0.63
Mutation Taster		=76/24	polymorphism

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: rs1933248311; hg19: chr3-132165348;