rs1553849919

Variant names:

• chr3-186572187-C-G
• rs1553849919
• NM_016306.6:c.161C>G
• DNAJB11 p.Pro54Arg

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_016306.6(DNAJB11):​c.161C>G​(p.Pro54Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAJB11 NM_016306.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.34
• Publications: 1 publications found

Genes affected

DNAJB11 (HGNC:14889): (DnaJ heat shock protein family (Hsp40) member B11) This gene encodes a soluble glycoprotein of the endoplasmic reticulum (ER) lumen that functions as a co-chaperone of binding immunoglobulin protein, a 70 kilodalton heat shock protein chaperone required for the proper folding and assembly of proteins in the ER. The encoded protein contains a highly conserved J domain of about 70 amino acids with a characteristic His-Pro-Asp (HPD) motif and may regulate the activity of binding immunoglobulin protein by stimulating ATPase activity. [provided by RefSeq, Mar 2014]

DNAJB11 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• polycystic kidney disease 6 with or without polycystic liver disease

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• ciliopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 3-186572187-C-G is Pathogenic according to our data. Variant chr3-186572187-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 549847.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016306.6. 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
	DNAJB11	NM_016306.6	MANE Select	c.161C>G	p.Pro54Arg	missense	Exon 2 of 10	NP_057390.1	Q9UBS4
	DNAJB11	NM_001378451.1		c.161C>G	p.Pro54Arg	missense	Exon 2 of 8	NP_001365380.1
	DNAJB11	NR_165638.1		n.339C>G		non_coding_transcript_exon	Exon 2 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJB11	ENST00000265028.8	TSL:1 MANE Select	c.161C>G	p.Pro54Arg	missense	Exon 2 of 10	ENSP00000265028.3	Q9UBS4
	DNAJB11	ENST00000439351.5	TSL:1	c.161C>G	p.Pro54Arg	missense	Exon 3 of 11	ENSP00000414398.1	Q9UBS4
	DNAJB11	ENST00000956498.1		c.161C>G	p.Pro54Arg	missense	Exon 2 of 10	ENSP00000626557.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Polycystic kidney disease 6 with or without polycystic liver disease (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.1	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.90
Mutation Taster		=21/79	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1553849919;

hg19: chr3-186289976;