rs139115934

chr20-32436018-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1102G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0087 (11 hom., cov: 32)
  • Exomes 𝑓: 0.011 (123 hom.)
• Consequence: ASXL1 NM_015338.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 3.67

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High AC in GnomAd at 1324 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASXL1	NM_015338.6	c.3306G>T	p.Glu1102Asp	missense_variant	13/13	ENST00000375687.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL1	ENST00000375687.10	c.3306G>T	p.Glu1102Asp	missense_variant	13/13	5	NM_015338.6	P1

Frequencies

GnomAD3 genomes AF: 0.00870 AC: 1324 AN: 152158 Hom.: 11 Cov.: 32

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.: 22 AF XY: 0.00912 AC XY: 1239 AN XY: 135918

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.: 31 AF XY: 0.0103 AC XY: 7481 AN XY: 727236

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.: 11 Cov.: 32 AF XY: 0.00932 AC XY: 694 AN XY: 74454

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.: 21

Bravo AF: 0.00653

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.0135 AC: 52

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0100 AC: 86

ExAC AF: 0.0101 AC: 1225

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0118

EpiControl AF: 0.0107

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

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

not specified Benign:2 Other:1

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	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	21
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	D
MetaRNN	Benign	0.0053	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;M;.;.
MutationTaster	Benign	0.73	N;N
PrimateAI	Benign	0.41	T
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	T
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

Other links and lift over

dbSNP: rs139115934; hg19: chr20-31023821; COSMIC: COSV60104067; COSMIC: COSV60104067;