Genetic Variant ASXL1:c.57+23dupG (chr20-32358849-A-AG) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP6_ModerateBS2_Supporting

The NM_015338.6(ASXL1):c.57+23dupG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000096 in 1,270,438 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

ASXL1
NM_015338.6 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0760

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

ASXL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP6

Variant 20-32358849-A-AG is Benign according to our data. Variant chr20-32358849-A-AG is described in ClinVar as Benign. ClinVar VariationId is 1901363.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 54 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ASXL1	NM_015338.6	MANE Select	c.57+23dupG	intron	N/A	NP_056153.2
ASXL1	NM_001164603.1		c.57+23dupG	intron	N/A	NP_001158075.1	Q498B9
ASXL1	NM_001363734.1		c.-459_-458insG	upstream_gene	N/A	NP_001350663.1	A0A2R8Y5U1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ASXL1	ENST00000375687.10	TSL:5 MANE Select	c.57+17_57+18insG	intron	N/A	ENSP00000364839.4	Q8IXJ9-1
ASXL1	ENST00000905973.1		c.57+17_57+18insG	intron	N/A	ENSP00000576032.1
ASXL1	ENST00000915088.1		c.57+17_57+18insG	intron	N/A	ENSP00000585147.1

Frequencies

GnomAD3 genomes

AF:

0.000362

AC:

AN:

149304

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000265

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000201

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:

0.0000683

AC:

AN:

102422

AF XY:

0.0000528

show subpopulations

Gnomad AFR exome

AF:

0.000656

Gnomad AMR exome

AF:

0.000215

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000181

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000293

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000607

AC:

AN:

1121020

Hom.:

Cov.:

AF XY:

0.0000590

AC XY:

AN XY:

559552

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

22534

American (AMR)

AF:

0.000133

AC:

AN:

30066

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21548

East Asian (EAS)

AF:

0.0000345

AC:

AN:

28990

South Asian (SAS)

AF:

0.0000429

AC:

AN:

69928

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3576

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

851516

Other (OTH)

AF:

0.000106

AC:

AN:

47376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000361

AC:

AN:

149418

Hom.:

Cov.:

AF XY:

0.000329

AC XY:

AN XY:

72962

show subpopulations

African (AFR)

AF:

0.00121

AC:

AN:

40626

American (AMR)

AF:

0.000264

AC:

AN:

15132

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3444

East Asian (EAS)

AF:

0.000202

AC:

AN:

4954

South Asian (SAS)

AF:

0.00

AC:

AN:

4724

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10120

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67140

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.000378

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.076

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

20-32358849-AG-AGG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over