chr11-73958343-AC-A

Variant names:

• chr11-73958343-AC-A
• rs777186025
• NM_153614.4:c.98delC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PP5_Moderate

The NM_153614.4(DNAJB13):​c.98delC​(p.Pro33ArgfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P33P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: DNAJB13 NM_153614.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.21
• Publications: 0 publications found

Genes affected

DNAJB13 (HGNC:30718): (DnaJ heat shock protein family (Hsp40) member B13) This gene encodes a member of the heat shock protein 40 co-chaperone family which is produced in large amounts in the testis and is located on the radial spokes of the axoneme in human sperm flagella and other flagellar structures. The encoded protein associates with the sperm annulus, as part of the septin complex, through direct interaction with septin 4, during sperm terminal differentiation. Naturally occurring mutations in this gene are associated with primary ciliary dyskinesia and male infertility. [provided by RefSeq, Apr 2017]

DNAJB13 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 34

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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 4 pathogenic variants in the truncated region.
• PP5: Variant 11-73958343-AC-A is Pathogenic according to our data. Variant chr11-73958343-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 2076101.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJB13	NM_153614.4	c.98delC	p.Pro33ArgfsTer2	frameshift_variant	Exon 2 of 8	ENST00000339764.6	NP_705842.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJB13	ENST00000339764.6	c.98delC	p.Pro33ArgfsTer2	frameshift_variant	Exon 2 of 8	1	NM_153614.4	ENSP00000344431.1
DNAJB13	ENST00000535730.1	n.142delC		non_coding_transcript_exon_variant	Exon 2 of 3	4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251448 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41490

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2100

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

May 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Pro33Argfs*2) in the DNAJB13 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAJB13 are known to be pathogenic (PMID: 27486783, 31650533). This variant is present in population databases (rs777186025, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with DNAJB13-related conditions. ClinVar contains an entry for this variant (Variation ID: 2076101). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=20/180	disease causing (fs/PTC)

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: rs777186025; hg19: chr11-73669388;