rs139115934

Positions:

chr20-32436018-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015338.6(ASXL1):c.3306G>T(p.Glu1102Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0105 in 1,614,144 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0087 ( 11 hom., cov: 32)

Exomes 𝑓: 0.011 ( 123 hom. )

Consequence

ASXL1
NM_015338.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.67

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 links:

ASXL1 (HGNC:):

ASXL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005330384).

BP6

Variant 20-32436018-G-T is Benign according to our data. Variant chr20-32436018-G-T is described in ClinVar as [Benign]. Clinvar id is 133595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32436018-G-T is described in Lovd as [Benign]. Variant chr20-32436018-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00869 (1324/152276) while in subpopulation NFE AF= 0.012 (816/68030). AF 95% confidence interval is 0.0113. There are 11 homozygotes in gnomad4. There are 694 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1324 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASXL1	NM_015338.6 linkuse as main transcript	c.3306G>T	p.Glu1102Asp	missense_variant	13/13	ENST00000375687.10	NP_056153.2	Q8IXJ9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASXL1	ENST00000375687.10 linkuse as main transcript	c.3306G>T	p.Glu1102Asp	missense_variant	13/13	5	NM_015338.6	ENSP00000364839.4		Q8IXJ9-1

Frequencies

GnomAD3 genomes

AF:

0.00870

AC:

1324

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.00950

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0306

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0120

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.00953

AC:

2397

AN:

251470

Hom.:

AF XY:

0.00912

AC XY:

1239

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00234

Gnomad AMR exome

AF:

0.00376

Gnomad ASJ exome

AF:

0.00754

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.0300

Gnomad NFE exome

AF:

0.0126

Gnomad OTH exome

AF:

0.0104

GnomAD4 exome

AF:

0.0107

AC:

15587

AN:

1461868

Hom.:

123

Cov.:

AF XY:

0.0103

AC XY:

7481

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00188

Gnomad4 AMR exome

AF:

0.00398

Gnomad4 ASJ exome

AF:

0.00865

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.0304

Gnomad4 NFE exome

AF:

0.0116

Gnomad4 OTH exome

AF:

0.00940

GnomAD4 genome

AF:

0.00869

AC:

1324

AN:

152276

Hom.:

Cov.:

AF XY:

0.00932

AC XY:

694

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00197

Gnomad4 AMR

AF:

0.00373

Gnomad4 ASJ

AF:

0.00950

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0306

Gnomad4 NFE

AF:

0.0120

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.0105

Hom.:

Bravo

AF:

0.00653

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.0135

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0100

AC:

ExAC

AF:

0.0101

AC:

1225

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0118

EpiControl

AF:

0.0107

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2020	This variant is associated with the following publications: (PMID: 29427188, 21346257, 20955399) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ASXL1: BP4, BS1, BS2 -

not specified

Benign:2Other:1

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Bohring-Opitz syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;T;T;.;T

Eigen

Benign

0.18

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

.;D;.;D;D

MetaRNN

Benign

0.0053

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M;M;.;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.9

N;.;.;.;N

REVEL

Benign

0.11

Sift

Benign

0.057

T;.;.;.;T

Sift4G

Benign

0.23

T;T;T;.;T

Polyphen

0.78

P;P;P;.;.

Vest4

0.44

MutPred

0.35

Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);.;.;

MPC

0.28

ClinPred

0.015

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.28

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over