chr11-73951137-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_153614.4(DNAJB13):c.68C>T(p.Ala23Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000297 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000030 ( 0 hom. )
Consequence
DNAJB13
NM_153614.4 missense, splice_region
NM_153614.4 missense, splice_region
Scores
8
7
4
Splicing: ADA: 0.9896
2
Clinical Significance
Conservation
PhyloP100: 4.45
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAJB13 | NM_153614.4 | c.68C>T | p.Ala23Val | missense_variant, splice_region_variant | 1/8 | ENST00000339764.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAJB13 | ENST00000339764.6 | c.68C>T | p.Ala23Val | missense_variant, splice_region_variant | 1/8 | 1 | NM_153614.4 | P1 | |
DNAJB13 | ENST00000535730.1 | n.112C>T | splice_region_variant, non_coding_transcript_exon_variant | 1/3 | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152238Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.0000301 AC: 44AN: 1461694Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26AN XY: 727136
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152356Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2AN XY: 74508
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 23 of the DNAJB13 protein (p.Ala23Val). This variant is present in population databases (rs185837848, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with DNAJB13-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of disorder (P = 0.0873);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at