chr20-32434666-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015338.6(ASXL1):c.1954G>A(p.Gly652Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00672 in 1,602,238 control chromosomes in the GnomAD database, including 401 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G652G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0087 ( 35 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 366 hom. )

Consequence

ASXL1
NM_015338.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.730

Publications

29 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=0.001430273).

BP6

Variant 20-32434666-G-A is Benign according to our data. Variant chr20-32434666-G-A is described in CliVar as Benign. Clinvar id is 133592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32434666-G-A is described in CliVar as Benign. Clinvar id is 133592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32434666-G-A is described in CliVar as Benign. Clinvar id is 133592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32434666-G-A is described in CliVar as Benign. Clinvar id is 133592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32434666-G-A is described in CliVar as Benign. Clinvar id is 133592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32434666-G-A is described in CliVar as Benign. Clinvar id is 133592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32434666-G-A is described in CliVar as Benign. Clinvar id is 133592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32434666-G-A is described in CliVar as Benign. Clinvar id is 133592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0656 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASXL1	NM_015338.6 link	c.1954G>A	p.Gly652Ser	missense_variant	Exon 13 of 13	ENST00000375687.10	NP_056153.2	Q8IXJ9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASXL1	ENST00000375687.10 link	c.1954G>A	p.Gly652Ser	missense_variant	Exon 13 of 13	5	NM_015338.6	ENSP00000364839.4		Q8IXJ9-1

Frequencies

GnomAD3 genomes

AF:

0.00870

AC:

1323

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0360

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.0719

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.0112

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00165

Gnomad OTH

AF:

0.0119

GnomAD2 exomes

AF:

0.0191

AC:

4317

AN:

225642

AF XY:

0.0155

show subpopulations

Gnomad AFR exome

AF:

0.00126

Gnomad AMR exome

AF:

0.0803

Gnomad ASJ exome

AF:

0.00741

Gnomad EAS exome

AF:

0.0624

Gnomad FIN exome

AF:

0.00959

Gnomad NFE exome

AF:

0.00235

Gnomad OTH exome

AF:

0.0176

GnomAD4 exome

AF:

0.00651

AC:

9435

AN:

1450008

Hom.:

366

Cov.:

AF XY:

0.00608

AC XY:

4382

AN XY:

720604

show subpopulations

African (AFR)

AF:

0.00112

AC:

AN:

33138

American (AMR)

AF:

0.0734

AC:

3173

AN:

43244

Ashkenazi Jewish (ASJ)

AF:

0.00762

AC:

198

AN:

25992

East Asian (EAS)

AF:

0.0938

AC:

3657

AN:

38970

South Asian (SAS)

AF:

0.00291

AC:

249

AN:

85480

European-Finnish (FIN)

AF:

0.0102

AC:

521

AN:

51222

Middle Eastern (MID)

AF:

0.00505

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.000967

AC:

1070

AN:

1106362

Other (OTH)

AF:

0.00837

AC:

501

AN:

59852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

605

1210

1814

2419

3024

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<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:

0.00874

AC:

1330

AN:

152230

Hom.:

Cov.:

AF XY:

0.00956

AC XY:

712

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00200

AC:

AN:

41536

American (AMR)

AF:

0.0367

AC:

561

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00980

AC:

AN:

3470

East Asian (EAS)

AF:

0.0716

AC:

370

AN:

5164

South Asian (SAS)

AF:

0.00560

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0112

AC:

119

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00165

AC:

112

AN:

68008

Other (OTH)

AF:

0.0113

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

142

213

284

355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00480

Hom.:

Bravo

AF:

0.0118

ESP6500AA

AF:

0.00195

AC:

ESP6500EA

AF:

0.00208

AC:

ExAC

AF:

0.0154

AC:

1854

Asia WGS

AF:

0.0520

AC:

180

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:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 31, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2Other:1

Oct 06, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Bohring-Opitz syndrome

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.052

T;T;T;.;T

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.56

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.72

.;T;.;T;T

MetaRNN

Benign

0.0014

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.74

N;N;N;.;.

PhyloP100

0.73

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.51

N;.;.;.;N

REVEL

Benign

0.017

Sift

Benign

0.65

T;.;.;.;T

Sift4G

Benign

0.49

T;T;T;.;T

Polyphen

0.0040

B;B;B;.;.

Vest4

0.20

MPC

0.059

ClinPred

0.0027

GERP RS

2.0

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

4.0

Varity_R

0.042

gMVP

0.10

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over