20-32434638-AG-A

Variant names:

• chr20-32434638-AG-A
• rs750318549
• NM_015338.6:c.1934delG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_015338.6(ASXL1):​c.1934delG​(p.Gly645ValfsTer58) 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. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G645G) has been classified as Likely benign.

• 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
• Publications: 56 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Illumina, ClinGen, Laboratory for Molecular Medicine, G2P, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 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 82 pathogenic variants in the truncated region.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL1	NM_015338.6	MANE Select	c.1934delG	p.Gly645ValfsTer58	frameshift	Exon 13 of 13	NP_056153.2
	ASXL1	NM_001363734.1		c.1751delG	p.Gly584ValfsTer58	frameshift	Exon 12 of 12	NP_001350663.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL1	ENST00000375687.10	TSL:5 MANE Select	c.1934delG	p.Gly645ValfsTer58	frameshift	Exon 13 of 13	ENSP00000364839.4
	ASXL1	ENST00000306058.9	TSL:1	c.1919delG	p.Gly640ValfsTer58	frameshift	Exon 12 of 12	ENSP00000305119.5
	ASXL1	ENST00000646985.1		c.1751delG	p.Gly584ValfsTer58	frameshift	Exon 12 of 12	ENSP00000495053.1

Frequencies

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

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

GnomAD2 exomes AF: 0.000286 AC: 61 AN: 213340 AF XY: 0.000256

Gnomad AFR exome AF: 0.000251

Gnomad AMR exome AF: 0.000192

Gnomad ASJ exome AF: 0.000110

Gnomad EAS exome AF: 0.000439

Gnomad FIN exome AF: 0.000329

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.000183

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000602 AC: 2 AN: 33224

American (AMR) AF: 0.000137 AC: 6 AN: 43680

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25998

East Asian (EAS) AF: 0.00 AC: 0 AN: 39262

South Asian (SAS) AF: 0.0000351 AC: 3 AN: 85578

European-Finnish (FIN) AF: 0.000136 AC: 7 AN: 51392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.0000280 AC: 31 AN: 1106764

Other (OTH) AF: 0.0000667 AC: 4 AN: 59964

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00 AC: 0 AN: 40956

American (AMR) AF: 0.00 AC: 0 AN: 15128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67468

Other (OTH) AF: 0.00 AC: 0 AN: 2060

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1
Mutation Taster		=7/193	disease causing

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: rs750318549; hg19: chr20-31022441; COSMIC: COSV60102180; COSMIC: COSV60102180;