20-32358816-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015338.6(ASXL1):c.41C>T(p.Ala14Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,336,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: ASXL1 NM_015338.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASXL1	NM_015338.6	c.41C>T	p.Ala14Val	missense_variant	1/13	ENST00000375687.10
ASXL1	NM_001164603.1	c.41C>T	p.Ala14Val	missense_variant	1/5
ASXL1	XM_006723727.4	c.41C>T	p.Ala14Val	missense_variant	1/12
ASXL1	XM_047439945.1	c.41C>T	p.Ala14Val	missense_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL1	ENST00000375687.10	c.41C>T	p.Ala14Val	missense_variant	1/13	5	NM_015338.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000181 AC: 2 AN: 110640 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 60874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000981

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1336904 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 659420

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000638

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 27, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with ASXL1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 14 of the ASXL1 protein (p.Ala14Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T;T;T;T
Eigen	Benign	0.00093
Eigen_PC	Benign	-0.034
FATHMM_MKL	Benign	0.47	N
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.0	L;.;L;.;L
MutationTaster	Benign	0.66	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.5	N;N;.;.;.
REVEL	Benign	0.17
Sift	Uncertain	0.0020	D;D;.;.;.
Sift4G	Uncertain	0.022	D;D;D;.;D
Polyphen		0.76	P;.;P;.;P
Vest4		0.18
MutPred		0.30		Loss of disorder (P = 0.063);Loss of disorder (P = 0.063);Loss of disorder (P = 0.063);Loss of disorder (P = 0.063);Loss of disorder (P = 0.063);
MVP		0.43
MPC		1.0
ClinPred		0.27	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1365687375; hg19: chr20-30946619;