20-32358788-CAGA-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_015338.6(ASXL1):c.25_27del(p.Lys9del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,460,560 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: ASXL1 NM_015338.6 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.55

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_015338.6
• BP6: Variant 20-32358788-CAGA-C is Benign according to our data. Variant chr20-32358788-CAGA-C is described in ClinVar as [Likely_benign]. Clinvar id is 1272899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASXL1	NM_015338.6	c.25_27del	p.Lys9del	inframe_deletion	1/13	ENST00000375687.10
ASXL1	NM_001164603.1	c.25_27del	p.Lys9del	inframe_deletion	1/5
ASXL1	XM_006723727.4	c.25_27del	p.Lys9del	inframe_deletion	1/12
ASXL1	XM_047439945.1	c.25_27del	p.Lys9del	inframe_deletion	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL1	ENST00000375687.10	c.25_27del	p.Lys9del	inframe_deletion	1/13	5	NM_015338.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000665 AC: 10 AN: 150372 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000997

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000889

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000418 AC: 47 AN: 112320 Hom.: 0 AF XY: 0.000453 AC XY: 28 AN XY: 61800

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.000139

Gnomad EAS exome AF: 0.00155

Gnomad SAS exome AF: 0.000519

Gnomad FIN exome AF: 0.000133

Gnomad NFE exome AF: 0.000525

Gnomad OTH exome AF: 0.000317

GnomAD4 exome AF: 0.000192 AC: 252 AN: 1310082 Hom.: 0 AF XY: 0.000194 AC XY: 125 AN XY: 645518

Gnomad4 AFR exome AF: 0.000267

Gnomad4 AMR exome AF: 0.000292

Gnomad4 ASJ exome AF: 0.0000902

Gnomad4 EAS exome AF: 0.000851

Gnomad4 SAS exome AF: 0.000226

Gnomad4 FIN exome AF: 0.000147

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.000152

GnomAD4 genome AF: 0.0000665 AC: 10 AN: 150478 Hom.: 0 Cov.: 31 AF XY: 0.0000680 AC XY: 5 AN XY: 73566

Gnomad4 AFR AF: 0.0000486

Gnomad4 AMR AF: 0.0000661

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000997

Gnomad4 NFE AF: 0.0000889

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jun 23, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2020	- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs752094508; hg19: chr20-30946591;