20-32436457-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015338.6(ASXL1):c.3745A>G(p.Met1249Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,614,152 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1249T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 6 hom. )

Consequence

ASXL1
NM_015338.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: -1.15

Publications

11 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002648145).

BP6

Variant 20-32436457-A-G is Benign according to our data. Variant chr20-32436457-A-G is described in ClinVar as Benign. ClinVar VariationId is 133580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00198 (302/152358) while in subpopulation NFE AF = 0.00238 (162/68032). AF 95% confidence interval is 0.00208. There are 0 homozygotes in GnomAd4. There are 160 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 302 AD gene.

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.3745A>G	p.Met1249Val	missense	Exon 13 of 13	NP_056153.2
	ASXL1	NM_001363734.1		c.3562A>G	p.Met1188Val	missense	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.3745A>G	p.Met1249Val	missense	Exon 13 of 13	ENSP00000364839.4
ASXL1	ENST00000306058.9	TSL:1	c.3730A>G	p.Met1244Val	missense	Exon 12 of 12	ENSP00000305119.5
ASXL1	ENST00000646985.1		c.3562A>G	p.Met1188Val	missense	Exon 12 of 12	ENSP00000495053.1

Frequencies

GnomAD3 genomes

AF:

0.00198

AC:

302

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00884

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00238

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00220

AC:

553

AN:

251180

AF XY:

0.00219

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0105

Gnomad NFE exome

AF:

0.00224

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00220

AC:

3216

AN:

1461794

Hom.:

Cov.:

AF XY:

0.00221

AC XY:

1606

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.000657

AC:

AN:

33480

American (AMR)

AF:

0.000470

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000788

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0107

AC:

569

AN:

53330

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00218

AC:

2427

AN:

1112008

Other (OTH)

AF:

0.00169

AC:

102

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

226

452

679

905

1131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<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:

0.00198

AC:

302

AN:

152358

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

160

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41578

American (AMR)

AF:

0.000588

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.00104

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00884

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00238

AC:

162

AN:

68032

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.00180

Hom.:

Bravo

AF:

0.00122

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00198

AC:

241

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Oct 26, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24728327, 27581359)

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ASXL1: BP4, BS1, BS2

Bohring-Opitz syndrome

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.0050

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.019

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.38

M_CAP

Benign

0.0021

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.69

PhyloP100

-1.1

PrimateAI

Benign

0.23

PROVEAN

Benign

0.070

REVEL

Benign

0.0030

Sift

Benign

0.50

Sift4G

Benign

0.48

Polyphen

0.0

Vest4

0.0070

MVP

0.061

MPC

0.058

ClinPred

0.0016

GERP RS

-8.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

0.98

Varity_R

0.038

gMVP

0.15

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over