Variant 20-32358776-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_015338.6(ASXL1):c.1A>C(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000169 in 1,186,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Consequence

ASXL1
NM_015338.6 initiator_codon

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.59

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASXL1	NM_015338.6 link	c.1A>C	p.Met1?	initiator_codon_variant	1/13	ENST00000375687.10	NP_056153.2	Q8IXJ9-1
ASXL1	NM_001164603.1 link	c.1A>C	p.Met1?	initiator_codon_variant	1/5		NP_001158075.1	Q498B9
ASXL1	XM_006723727.4 link	c.1A>C	p.Met1?	initiator_codon_variant	1/12		XP_006723790.1
ASXL1	XM_047439945.1 link	c.1A>C	p.Met1?	initiator_codon_variant	1/11		XP_047295901.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASXL1	ENST00000375687.10 link	c.1A>C	p.Met1?	initiator_codon_variant	1/13	5	NM_015338.6	ENSP00000364839.4		Q8IXJ9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000169

AC:

AN:

1186718

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

583718

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000563

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000105

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 23, 2024

Initiation codon variant in a gene for which loss of function is a known mechanism of disease; however an alternative Methionine exists downstream and the actual effect of this variant on protein function is unknown in the absence of functional studies; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Benign

0.91

DEOGEN2

Benign

0.17

T;T;T;T;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.32

LIST_S2

Uncertain

0.90

.;D;D;.;.

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.84

D;D;D;D;D

MetaSVM

Benign

-1.1

PROVEAN

Benign

-1.1

N;N;.;.;.

REVEL

Benign

0.15

Sift

Pathogenic

0.0

D;D;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;.;D

Polyphen

0.019

B;.;B;.;B

Vest4

0.63

MutPred

1.0

Loss of methylation at K4 (P = 0.0536);Loss of methylation at K4 (P = 0.0536);Loss of methylation at K4 (P = 0.0536);Loss of methylation at K4 (P = 0.0536);Loss of methylation at K4 (P = 0.0536);

MVP

0.30

ClinPred

0.94

GERP RS

0.13

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.33

gMVP

0.64

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over