chr20-32434638-AG-A

Position:

• chr20-32434638-AG-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PVS1_Strong BP6 BS2_Supporting

The NM_015338.6(ASXL1):​c.1934delG​(p.Gly645fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000372 in 1,451,584 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in Lovd as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ASXL1 NM_015338.6 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.06

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
• BP6: Variant 20-32434638-AG-A is Benign according to our data. Variant chr20-32434638-AG-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAdExome4 at 54 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASXL1	NM_015338.6	c.1934delG	p.Gly645fs	frameshift_variant	13/13	ENST00000375687.10	NP_056153.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASXL1	ENST00000375687.10	c.1934delG	p.Gly645fs	frameshift_variant	13/13	5	NM_015338.6	ENSP00000364839.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 150616 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000372 AC: 54 AN: 1451584 Hom.: 0 Cov.: 30 AF XY: 0.0000485 AC XY: 35 AN XY: 721502

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.000137

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000351

Gnomad4 FIN exome AF: 0.000136

Gnomad4 NFE exome AF: 0.0000280

Gnomad4 OTH exome AF: 0.0000667

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 150616 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73508

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

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: rs750318549; hg19: chr20-31022441;