10-125836761-CAG-C
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_018180.3(DHX32):c.2156_2157delCT(p.Pro719fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000966 in 1,614,164 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000098 ( 0 hom. )
Consequence
DHX32
NM_018180.3 frameshift
NM_018180.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.87
Genes affected
DHX32 (HGNC:16717): (DEAH-box helicase 32 (putative)) DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this DEAD box protein family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a member of this family. The function of this member has not been determined. Alternative splicing of this gene generates 2 transcript variants, but the full length nature of one of the variants has not been defined. [provided by RefSeq, Jul 2008]
BCCIP (HGNC:978): (BRCA2 and CDKN1A interacting protein) This gene product was isolated on the basis of its interaction with BRCA2 and p21 proteins. It is an evolutionarily conserved nuclear protein with multiple interacting domains. The N-terminal half shares moderate homology with regions of calmodulin and M-calpain, suggesting that it may also bind calcium. Functional studies indicate that this protein may be an important cofactor for BRCA2 in tumor suppression, and a modulator of CDK2 kinase activity via p21. This protein has also been implicated in the regulation of BRCA2 and RAD51 nuclear focus formation, double-strand break-induced homologous recombination, and cell cycle progression. Multiple transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DHX32 | ENST00000284690.4 | c.2156_2157delCT | p.Pro719fs | frameshift_variant | 11/11 | 1 | NM_018180.3 | ENSP00000284690.3 | ||
| DHX32 | ENST00000368721.5 | c.1028_1029delCT | p.Pro343fs | frameshift_variant | 8/8 | 1 | ENSP00000357710.1 | |||
| BCCIP | ENST00000368759.5 | c.774+2816_774+2817delAG | intron_variant | 1 | ENSP00000357748.5 | |||||
| BCCIP | ENST00000299130.7 | c.774+2816_774+2817delAG | intron_variant | 1 | ENSP00000299130.3 |
Frequencies
GnomAD3 genomes 0.0000854 AC: 13AN: 152178Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000163 AC: 41AN: 251462Hom.: 0 AF XY: 0.000213 AC XY: 29AN XY: 135912
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GnomAD4 exome AF: 0.0000978 AC: 143AN: 1461868Hom.: 0 AF XY: 0.000113 AC XY: 82AN XY: 727242
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GnomAD4 genome 0.0000854 AC: 13AN: 152296Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6AN XY: 74470
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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 | Labcorp Genetics (formerly Invitae), Labcorp | Nov 29, 2024 | This sequence change creates a premature translational stop signal (p.Pro719Argfs*6) in the DHX32 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 25 amino acid(s) of the DHX32 protein. This variant is present in population databases (rs755174172, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DHX32-related conditions. ClinVar contains an entry for this variant (Variation ID: 1896071). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at