chr20-32358849-AG-A

Variant names:

• chr20-32358849-AG-A
• rs757765039
• NM_015338.6:c.57+23delG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_015338.6(ASXL1):​c.57+23delG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000714 in 1,121,022 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: ASXL1 NM_015338.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0760
• Publications: 0 publications found

Genes affected

ASXL1 (HGNC:18318): (ASXL transcriptional regulator 1) This gene is similar to the Drosophila additional sex combs gene, which encodes a chromatin-binding protein required for normal determination of segment identity in the developing embryo. The protein is a member of the Polycomb group of proteins, which are necessary for the maintenance of stable repression of homeotic and other loci. The protein is thought to disrupt chromatin in localized areas, enhancing transcription of certain genes while repressing the transcription of other genes. The protein encoded by this gene functions as a ligand-dependent co-activator for retinoic acid receptor in cooperation with nuclear receptor coactivator 1. Mutations in this gene are associated with myelodysplastic syndromes and chronic myelomonocytic leukemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

ASXL1 Gene-Disease associations (from GenCC):

• Bohring-Opitz syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Laboratory for Molecular Medicine, Orphanet, G2P, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS2: High AC in GnomAdExome4 at 8 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015338.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL1	NM_015338.6	MANE Select	c.57+23delG		intron	N/A	NP_056153.2
	ASXL1	NM_001164603.1		c.57+23delG		intron	N/A	NP_001158075.1	Q498B9
	ASXL1	NM_001363734.1		c.-458delG		upstream_gene	N/A	NP_001350663.1	A0A2R8Y5U1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL1	ENST00000375687.10	TSL:5 MANE Select	c.57+18delG		intron	N/A	ENSP00000364839.4	Q8IXJ9-1
	ASXL1	ENST00000905973.1		c.57+18delG		intron	N/A	ENSP00000576032.1
	ASXL1	ENST00000915088.1		c.57+18delG		intron	N/A	ENSP00000585147.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000714 AC: 8 AN: 1121022 Hom.: 0 Cov.: 33 AF XY: 0.0000107 AC XY: 6 AN XY: 559554

African (AFR) AF: 0.00 AC: 0 AN: 22534

American (AMR) AF: 0.00 AC: 0 AN: 30066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21548

East Asian (EAS) AF: 0.00 AC: 0 AN: 28990

South Asian (SAS) AF: 0.0000143 AC: 1 AN: 69928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3576

European-Non Finnish (NFE) AF: 0.00000587 AC: 5 AN: 851518

Other (OTH) AF: 0.0000422 AC: 2 AN: 47376

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.076

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: rs757765039; hg19: chr20-30946652; COSMIC: COSV100038456; COSMIC: COSV100038456;