rs146464648

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.4189G>A(p.Gly1397Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,614,200 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1397A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 11 hom. )

Consequence

ASXL1
NM_015338.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 8.14

Publications

19 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=0.0074142218).

BP6

Variant 20-32436901-G-A is Benign according to our data. Variant chr20-32436901-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00149 (227/152326) while in subpopulation SAS AF = 0.00913 (44/4818). AF 95% confidence interval is 0.00699. There are 1 homozygotes in GnomAd4. There are 115 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 227 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASXL1	NM_015338.6 link	c.4189G>A	p.Gly1397Ser	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.4189G>A	p.Gly1397Ser	missense_variant	Exon 13 of 13	5	NM_015338.6	ENSP00000364839.4		Q8IXJ9-1

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

226

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00912

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00166

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00201

AC:

506

AN:

251464

AF XY:

0.00246

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000954

Gnomad ASJ exome

AF:

0.00367

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00185

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00181

AC:

2640

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

1480

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33480

American (AMR)

AF:

0.00116

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00333

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00735

AC:

634

AN:

86258

European-Finnish (FIN)

AF:

0.000169

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00416

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00156

AC:

1731

AN:

1112012

Other (OTH)

AF:

0.00154

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

192

384

576

768

960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

204

272

340

<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:

0.00149

AC:

227

AN:

152326

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

115

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41576

American (AMR)

AF:

0.00202

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00913

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00168

AC:

114

AN:

68026

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.00174

Hom.:

Bravo

AF:

0.00132

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00207

AC:

251

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00294

EpiControl

AF:

0.00261

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely 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

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ASXL1: BP4, BS1, BS2 -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 09, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24448499, 19609284, 28386644, 24728327) -

ASXL1-related disorder

Benign:1

Feb 13, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.066

T;T;T;.;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

.;D;.;D;D

M_CAP

Benign

0.0050

MetaRNN

Benign

0.0074

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L;L;.;.

PhyloP100

8.1

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.52

N;.;.;.;N

REVEL

Benign

0.11

Sift

Benign

0.043

D;.;.;.;D

Sift4G

Benign

0.42

T;T;T;.;T

Polyphen

0.79

P;P;P;.;.

Vest4

0.12

MVP

0.45

MPC

0.086

ClinPred

0.038

GERP RS

4.7

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Varity_R

0.12

gMVP

0.25

Mutation Taster

=97/3

polymorphism

(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