rs3746609

Positions:

• chr20-32434666-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/20 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 Benign.

• Frequency:
  • Genomes: 𝑓 0.0087 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (366 hom.)
• Consequence: ASXL1 NM_015338.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.730

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=0.001430273).
• BP6: Variant 20-32434666-G-A is Benign according to our data. Variant chr20-32434666-G-A is described in ClinVar 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 Lovd as [Benign]. Variant chr20-32434666-G-A is described in Lovd as [Likely_benign].
• 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/exons	MANE	UniProt
ASXL1	NM_015338.6	c.1954G>A	p.Gly652Ser	missense_variant	13/13	ENST00000375687.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL1	ENST00000375687.10	c.1954G>A	p.Gly652Ser	missense_variant	13/13	5	NM_015338.6	P1

Frequencies

GnomAD3 genomes AF: 0.00870 AC: 1323 AN: 152112 Hom.: 32 Cov.: 32

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

GnomAD3 exomes AF: 0.0191 AC: 4317 AN: 225642 Hom.: 173 AF XY: 0.0155 AC XY: 1931 AN XY: 124220

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 SAS exome AF: 0.00248

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.: 30 AF XY: 0.00608 AC XY: 4382 AN XY: 720604

Gnomad4 AFR exome AF: 0.00112

Gnomad4 AMR exome AF: 0.0734

Gnomad4 ASJ exome AF: 0.00762

Gnomad4 EAS exome AF: 0.0938

Gnomad4 SAS exome AF: 0.00291

Gnomad4 FIN exome AF: 0.0102

Gnomad4 NFE exome AF: 0.000967

Gnomad4 OTH exome AF: 0.00837

GnomAD4 genome AF: 0.00874 AC: 1330 AN: 152230 Hom.: 35 Cov.: 32 AF XY: 0.00956 AC XY: 712 AN XY: 74440

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.0367

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.0716

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.0112

Gnomad4 NFE AF: 0.00165

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.00418 Hom.: 32

Bravo AF: 0.0118

ESP6500AA AF: 0.00195 AC: 8

ESP6500EA AF: 0.00208 AC: 17

ExAC AF: 0.0154 AC: 1854

Asia WGS AF: 0.0520 AC: 180 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -

not specified Benign:2 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 06, 2015	- -

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	Benign	0.069
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
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	D
MetaRNN	Benign	0.0014	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.74	N;N;N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
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	T
GERP RS		2.0
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		4.0
Varity_R		0.042
gMVP		0.10

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: rs3746609; hg19: chr20-31022469; COSMIC: COSV60103026; COSMIC: COSV60103026;