Variant 20-32358804-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015338.6(ASXL1):c.29A>G(p.Glu10Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000767 in 1,303,098 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: 7.7e-7 ( 0 hom. )

Consequence

ASXL1
NM_015338.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.00

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10207394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASXL1	NM_015338.6 linkuse as main transcript	c.29A>G	p.Glu10Gly	missense_variant	1/13	ENST00000375687.10	NP_056153.2	Q8IXJ9-1
ASXL1	NM_001164603.1 linkuse as main transcript	c.29A>G	p.Glu10Gly	missense_variant	1/5		NP_001158075.1	Q498B9
ASXL1	XM_006723727.4 linkuse as main transcript	c.29A>G	p.Glu10Gly	missense_variant	1/12		XP_006723790.1
ASXL1	XM_047439945.1 linkuse as main transcript	c.29A>G	p.Glu10Gly	missense_variant	1/11		XP_047295901.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASXL1	ENST00000375687.10 linkuse as main transcript	c.29A>G	p.Glu10Gly	missense_variant	1/13	5	NM_015338.6	ENSP00000364839.4		Q8IXJ9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.67e-7

AC:

AN:

1303098

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

642334

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

9.75e-7

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

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2022

The c.29A>G (p.E10G) alteration is located in exon 1 (coding exon 1) of the ASXL1 gene. This alteration results from a A to G substitution at nucleotide position 29, causing the glutamic acid (E) at amino acid position 10 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.048

T;T;T;T;T

Eigen

Benign

-0.075

Eigen_PC

Benign

-0.098

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.77

.;T;T;.;.

M_CAP

Benign

0.050

MetaRNN

Benign

0.10

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.55

N;.;N;.;N

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

0.32

N;N;.;.;.

REVEL

Benign

0.074

Sift

Benign

0.10

T;T;.;.;.

Sift4G

Benign

0.57

T;T;T;.;T

Polyphen

0.95

P;.;P;.;P

Vest4

0.19

MutPred

0.18

Loss of methylation at K6 (P = 0.0472);Loss of methylation at K6 (P = 0.0472);Loss of methylation at K6 (P = 0.0472);Loss of methylation at K6 (P = 0.0472);Loss of methylation at K6 (P = 0.0472);

MVP

0.41

MPC

1.4

ClinPred

0.51

GERP RS

1.5

Varity_R

0.16

gMVP

0.81

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