20-32434638-AGG-AGGG

Position:

• chr20-32434638-AGG-AGGG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_015338.6(ASXL1):​c.1934dupG​(p.Gly646fs) 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• 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:12
• 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 Pathogenic. Variant got 12 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.
• PP5: Variant 20-32434638-A-AG is Pathogenic according to our data. Variant chr20-32434638-A-AG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 426927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASXL1	NM_015338.6	c.1934dupG	p.Gly646fs	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.1934dupG	p.Gly646fs	frameshift_variant	13/13	5	NM_015338.6	ENSP00000364839.4

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

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

Gnomad4 AFR exome AF: 0.000241

Gnomad4 AMR exome AF: 0.000297

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.000331

Gnomad4 SAS exome AF: 0.000280

Gnomad4 FIN exome AF: 0.000758

Gnomad4 NFE exome AF: 0.000421

Gnomad4 OTH exome AF: 0.000334

GnomAD4 genome AF: 0.000644 AC: 97 AN: 150528 Hom.: 0 Cov.: 32 AF XY: 0.000613 AC XY: 45 AN XY: 73462

Gnomad4 AFR AF: 0.000220

Gnomad4 AMR AF: 0.000198

Gnomad4 ASJ AF: 0.00174

Gnomad4 EAS AF: 0.000781

Gnomad4 SAS AF: 0.000422

Gnomad4 FIN AF: 0.000382

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.000486

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bohring-Opitz syndrome Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 18, 2020	This variant was identified as de novo (maternity and paternity confirmed). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Mar 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Nov 10, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 25, 2024	Variant summary: ASXL1 c.1934dupG (p.Gly646TrpfsX12) located in the last exon results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been reported in association with Bohring-Opitz syndrome in the HGMD/LOVD databases. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1934dupG has been reported in the literature as a de-novo variant in at-least two individuals affected with Bohring-Opitz Syndrome (example, Kibe_2017, Urreizti_2018). As this variant is located in a homopolymer tract of guanines it is prone to replication slippage and could be overrepresented as sequencing artifacts. This variant has also been reported to be a common cancer-associated ASXL1 variant in settings of myeloid malignancies (Van Ness_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 426927). Based on the evidence outlined above, in settings where somatic mosaicism, clonal hematopoiesis of indeterminate potential (CHIP) and technical artifacts of analysis are ruled out, the variant was classified as pathogenic in association with Bohring-Opitz Syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jun 14, 2022	ACMG classification criteria: PVS1 very strong, PS4 supporting, PM2 moderated, PM6 strong -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 22, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 27, 2021	This variant causes a frameshift at codon 646 which results in the creation of a premature stop codon and the loss of 896 amino acids. Multiple truncating variants in this region have been reported in patients with Bohring-Opitz syndrome (PMID: 21706002, 28229513). This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene (PMID: 29681105, 30147881). This variant has been observed in the general population at a frequency higher than expected for a pathogenic variant in this gene. However, this frequency may represent acquired somatic mosaicism which has been reported to occur with age during hematopoietic clonal expansion of cells with pathogenic ASXL1 variants in healthy individuals. (https://gnomad.broadinstitute.org/, PMID 28229513)This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2021	Frameshift variant predicted to result in protein truncation, as the last 896 amino acids are replaced with 11 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 28832022, 33502020, 32381577, 28229513, 20596031, 20693432, 30013160, 29681105, 30147881) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 23, 2023	This sequence change creates a premature translational stop signal (p.Gly646Trpfs*12) in the ASXL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 896 amino acid(s) of the ASXL1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Bohring-Opitz syndrome (PMID: 29681105, 30147881). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 426927). For these reasons, this variant has been classified as Pathogenic. -

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

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ASXL1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2024

The ASXL1 c.1934dupG variant is predicted to result in a frameshift and premature protein termination (p.Gly646Trpfs*12). This variant has been reported as causative for Bohring-Opitz syndrome in two patients in the literature (Kibe et al. 2018. PubMed ID: 29681105; Urreizti et al. 2018. PubMed ID: 30147881). It has also been reported as a de novo finding in a patient tested at PreventionGenetics. This variant is present in gnomAD in 0.064% of alleles in individuals of European (Non-Finnish) descent in gnomAD, but it fails data-quality filters, indicative of sequencing errors common to this type of homopolymer (repeat of G nucleotides). Heterozygous frameshift variants in ASXL1 are expected to be pathogenic for autosomal dominant Bohring-Opitz syndrome. This variant is interpreted as pathogenic. -

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;