chr18-33616691-GAA-G
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_030632.3(ASXL3):c.137+9017_137+9018del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 152,258 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)
Consequence
ASXL3
NM_030632.3 intron
NM_030632.3 intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.62
Genes affected
ASXL3 (HGNC:29357): (ASXL transcriptional regulator 3) This gene encodes a protein containing a plant homeodomain (PHD) zinc finger domain that plays a role in the regulation of gene transcription. The encoded protein has been shown to negatively regulate lipogenesis by binding to and inhibiting the transcriptional activity of two nuclear hormone receptors, oxysterols receptor LXR-alpha (LXRalpha) and thyroid hormone receptor beta (TRbeta). The encoded protein may also inhibit histone deubiquitination. Mutations in this gene have been identified in human patients with Bainbridge-Ropers syndrome, which is characterized by feeding difficulties, developmental delay and other features. [provided by RefSeq, May 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00127 (194/152258) while in subpopulation AFR AF= 0.00435 (181/41564). AF 95% confidence interval is 0.00384. There are 0 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High AC in GnomAd at 194 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASXL3 | NM_030632.3 | c.137+9017_137+9018del | intron_variant | ENST00000269197.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASXL3 | ENST00000269197.12 | c.137+9017_137+9018del | intron_variant | 5 | NM_030632.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00128 AC: 194AN: 152140Hom.: 0 Cov.: 32
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We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? AF: 0.00127 AC: 194AN: 152258Hom.: 0 Cov.: 32 AF XY: 0.00134 AC XY: 100AN XY: 74438
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
ASXL3-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 09, 2023 | The ASXL3 c.137+9017_137+9018delAA variant is predicted to result in an intronic deletion. In a study of individuals with ASXL3-related syndrome, this variant was not reported in an affected individual, however was noted as loss of function variant (it is not clear which transcript was used) present in gnomAD databalse (Table S7, Schirwani et al 2021. PubMed ID: 34436830). This variant is reported in 0.45% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-31196655-GAA-G). . Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
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