11-73958340-ACCA-GAG

Variant names:

• chr11-73958340-ACCA-GAG
• NM_153614.4:c.92_95delACCAinsGAG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_153614.4(DNAJB13):​c.92_95delACCAinsGAG​(p.His31ArgfsTer4) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAJB13 NM_153614.4 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.19

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 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. Fraction of 0.903 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-73958340-ACCA-GAG is Pathogenic according to our data. Variant chr11-73958340-ACCA-GAG is described in ClinVar as [Pathogenic]. Clinvar id is 1805029.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.92_95delACCAinsGAG	p.His31ArgfsTer4	frameshift_variant, missense_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.92_95delACCAinsGAG	p.His31ArgfsTer4	frameshift_variant, missense_variant	Exon 2 of 8	1	NM_153614.4	ENSP00000344431.1
DNAJB13	ENST00000535730.1	n.136_139delACCAinsGAG		non_coding_transcript_exon_variant	Exon 2 of 3	4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 34 Pathogenic:1

Oct 11, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with primary ciliary dyskinesia 34 (MIM#617091). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is located within the first 102 nucleotides and is predicted to escape NMD). (SP) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0703 - Other NMD-escape variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Two variants which create a termination codon within the first 102 nucleotides have been observed as homozygous in individuals with primary ciliary dyskinesia (ClinVar, personal correspondence, PMID: 27486783). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0903 - This variant has limited evidence for segregation with disease. This variant was shown by this laboratory to segregate in three affected siblings from the same family. (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-73669385;