20-32436833-TG-TGG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_015338.6(ASXL1):c.4127dupG(p.Pro1377SerfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ASXL1
NM_015338.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: -0.629

Publications

0 publications found

Variant links:

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

ASXL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 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 7 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 20-32436833-T-TG is Pathogenic according to our data. Variant chr20-32436833-T-TG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 521420.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL1	NM_015338.6	MANE Select	c.4127dupG	p.Pro1377SerfsTer3	frameshift	Exon 13 of 13	NP_056153.2
	ASXL1	NM_001363734.1		c.3944dupG	p.Pro1316SerfsTer3	frameshift	Exon 12 of 12	NP_001350663.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ASXL1	ENST00000375687.10	TSL:5 MANE Select	c.4127dupG	p.Pro1377SerfsTer3	frameshift	Exon 13 of 13	ENSP00000364839.4
ASXL1	ENST00000306058.9	TSL:1	c.4112dupG	p.Pro1372SerfsTer3	frameshift	Exon 12 of 12	ENSP00000305119.5
ASXL1	ENST00000646985.1		c.3944dupG	p.Pro1316SerfsTer3	frameshift	Exon 12 of 12	ENSP00000495053.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727238

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Feb 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the ASXL1 protein. Other variant(s) that disrupt this region (p.Glu1400*) have been determined to be pathogenic (PMID: 31969346). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in individual(s) with clinical features of Bohring-Opitz syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 521420). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Pro1377Serfs*3) in the ASXL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 165 amino acid(s) of the ASXL1 protein.

Oct 16, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge

Inborn genetic diseases

Pathogenic:1

Dec 09, 2016

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Bohring-Opitz syndrome;C3463824:Myelodysplastic syndrome

Pathogenic:1

May 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.63

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over