rs146464648

chr20-32436901-G-Achr20-32436901-G-C

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.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. 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 8.14

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=0.0074142218).
• BP6: Variant 20-32436901-G-A is Benign according to our data. Variant chr20-32436901-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 133598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32436901-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 226 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASXL1	NM_015338.6	c.4189G>A	p.Gly1397Ser	missense_variant	13/13	ENST00000375687.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL1	ENST00000375687.10	c.4189G>A	p.Gly1397Ser	missense_variant	13/13	5	NM_015338.6	P1

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 226 AN: 152208 Hom.: 1 Cov.: 32

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

GnomAD3 exomes AF: 0.00201 AC: 506 AN: 251464 Hom.: 2 AF XY: 0.00246 AC XY: 334 AN XY: 135910

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 SAS exome AF: 0.00666

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.: 11 Cov.: 41 AF XY: 0.00204 AC XY: 1480 AN XY: 727238

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00333

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00735

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00156

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152326 Hom.: 1 Cov.: 32 AF XY: 0.00154 AC XY: 115 AN XY: 74484

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00202

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00913

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00168

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00185 Hom.: 1

Bravo AF: 0.00132

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00207 AC: 251

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00261

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

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	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ASXL1: BP4, BS1, BS2 -
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	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2021	This variant is associated with the following publications: (PMID: 24448499, 19609284, 28386644, 24728327) -

ASXL1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2024

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	23
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	D
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.0074	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;L;.;.
MutationTaster	Benign	0.91	D;D
PrimateAI	Benign	0.31	T
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	T
GERP RS		4.7
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.12
gMVP		0.25

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: rs146464648; hg19: chr20-31024704; COSMIC: COSV60104786; COSMIC: COSV60104786;