20-32434638-AGGGGG-AGGGGGG

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_015338.6(ASXL1):​c.1934dupG​(p.Gly646TrpfsTer12) variant causes a frameshift change. The variant allele was found at a frequency of 0.000428 in 1,601,778 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G645G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: ASXL1 NM_015338.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:3
• Conservation: PhyloP100: 6.06
• Publications: 59 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Laboratory for Molecular Medicine, G2P, Illumina

ACMG classification

Our verdict: Pathogenic. The variant received 16 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 87 pathogenic variants in the truncated region.
• PP5: Variant 20-32434638-A-AG is Pathogenic according to our data. Variant chr20-32434638-A-AG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 426927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1934dupG	p.Gly646TrpfsTer12	frameshift	Exon 13 of 13	NP_056153.2
	ASXL1	NM_001363734.1		c.1751dupG	p.Gly585TrpfsTer12	frameshift	Exon 12 of 12	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.1934dupG	p.Gly646TrpfsTer12	frameshift	Exon 13 of 13	ENSP00000364839.4	Q8IXJ9-1
	ASXL1	ENST00000306058.9	TSL:1	c.1919dupG	p.Gly641TrpfsTer12	frameshift	Exon 12 of 12	ENSP00000305119.5	Q76L82
	ASXL1	ENST00000905973.1		c.1931dupG	p.Gly645TrpfsTer12	frameshift	Exon 12 of 12	ENSP00000576032.1

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 97 AN: 150528 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00174

Gnomad EAS AF: 0.000781

Gnomad SAS AF: 0.000422

Gnomad FIN AF: 0.000382

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.000486

GnomAD2 exomes AF: 0.000525 AC: 112 AN: 213340 AF XY: 0.000452

Gnomad AFR exome AF: 0.000501

Gnomad AMR exome AF: 0.000287

Gnomad ASJ exome AF: 0.000439

Gnomad EAS exome AF: 0.000439

Gnomad FIN exome AF: 0.000164

Gnomad NFE exome AF: 0.000686

Gnomad OTH exome AF: 0.000916

GnomAD4 exome AF: 0.000405 AC: 588 AN: 1451250 Hom.: 0 Cov.: 30 AF XY: 0.000525 AC XY: 379 AN XY: 721262

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

African (AFR) AF: 0.000241 AC: 8 AN: 33224

American (AMR) AF: 0.000297 AC: 13 AN: 43708

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 25994

East Asian (EAS) AF: 0.000331 AC: 13 AN: 39252

South Asian (SAS) AF: 0.000280 AC: 24 AN: 85598

European-Finnish (FIN) AF: 0.000758 AC: 39 AN: 51418

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5724

European-Non Finnish (NFE) AF: 0.000421 AC: 466 AN: 1106398

Other (OTH) AF: 0.000334 AC: 20 AN: 59934

⚠️ 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 AF: 0.000644 AC: 97 AN: 150528 Hom.: 0 Cov.: 32 AF XY: 0.000613 AC XY: 45 AN XY: 73462

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

African (AFR) AF: 0.000220 AC: 9 AN: 40940

American (AMR) AF: 0.000198 AC: 3 AN: 15120

Ashkenazi Jewish (ASJ) AF: 0.00174 AC: 6 AN: 3450

East Asian (EAS) AF: 0.000781 AC: 4 AN: 5122

South Asian (SAS) AF: 0.000422 AC: 2 AN: 4740

European-Finnish (FIN) AF: 0.000382 AC: 4 AN: 10468

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

European-Non Finnish (NFE) AF: 0.00101 AC: 68 AN: 67414

Other (OTH) AF: 0.000486 AC: 1 AN: 2058

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000632 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Bohring-Opitz syndrome (7)
3	-	-	not provided (3)
2	-	-	ASXL1-related disorder (2)
1	-	-	Abnormal brain morphology (1)
-	-	-	Diffuse midline glioma, H3 K27M-mutant (1)
-	-	-	Ependymoma (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1
Mutation Taster		=2/198	disease causing (ClinVar)

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: COSV60102155; COSMIC: COSV60102155;