Genetic Variant NM_016306.6:c.45C>G (chr3-186570942-C-G) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_016306.6(DNAJB11):c.45C>G(p.Tyr15*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,768 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. Synonymous variant affecting the same amino acid position (i.e. Y15Y) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DNAJB11
NM_016306.6 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.22

Publications

0 publications found

Variant links:

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: ClinGen, Orphanet
polycystic kidney disease 6 with or without polycystic liver disease
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
ciliopathy
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

DNAJB11 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 21 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAJB11	NM_016306.6	MANE Select	c.45C>G	p.Tyr15*	stop_gained	Exon 1 of 10	NP_057390.1	Q9UBS4
DNAJB11	NM_001378451.1		c.45C>G	p.Tyr15*	stop_gained	Exon 1 of 8	NP_001365380.1
DNAJB11	NR_165638.1		n.223C>G		non_coding_transcript_exon	Exon 1 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAJB11	ENST00000265028.8	TSL:1 MANE Select	c.45C>G	p.Tyr15*	stop_gained	Exon 1 of 10	ENSP00000265028.3	Q9UBS4
DNAJB11	ENST00000439351.5	TSL:1	c.45C>G	p.Tyr15*	stop_gained	Exon 2 of 11	ENSP00000414398.1	Q9UBS4
DNAJB11	ENST00000956498.1		c.45C>G	p.Tyr15*	stop_gained	Exon 1 of 10	ENSP00000626557.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447768

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719394

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32922

American (AMR)

AF:

0.00

AC:

AN:

43086

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25792

East Asian (EAS)

AF:

0.00

AC:

AN:

38292

South Asian (SAS)

AF:

0.00

AC:

AN:

83794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1105482

Other (OTH)

AF:

0.00

AC:

AN:

59840

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.95

PhyloP100

1.2

Vest4

0.20

GERP RS

5.4

PromoterAI

-0.023

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Mutation Taster

=14/186

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over