20-32436404-C-A

Variant summary

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

The NM_015338.6(ASXL1):​c.3692C>A​(p.Ser1231Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1231F) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

ASXL1
NM_015338.6 missense

Scores

6
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.23
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]

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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=0.15643328).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ASXL1NM_015338.6 linkuse as main transcriptc.3692C>A p.Ser1231Tyr missense_variant 13/13 ENST00000375687.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ASXL1ENST00000375687.10 linkuse as main transcriptc.3692C>A p.Ser1231Tyr missense_variant 13/135 NM_015338.6 P1Q8IXJ9-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Benign
0.22
T;T;T;.;T
Eigen
Benign
0.080
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.85
.;D;.;D;D
M_CAP
Benign
0.0061
T
MetaRNN
Benign
0.16
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.2
M;M;M;.;.
MutationTaster
Benign
0.68
N;N
PrimateAI
Benign
0.30
T
PROVEAN
Uncertain
-2.5
D;.;.;.;D
REVEL
Benign
0.049
Sift
Uncertain
0.0020
D;.;.;.;D
Sift4G
Uncertain
0.059
T;T;T;.;T
Polyphen
0.77
P;P;P;.;.
Vest4
0.28
MutPred
0.20
Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);.;.;
MVP
0.42
MPC
0.15
ClinPred
0.89
D
GERP RS
3.6
Varity_R
0.093
gMVP
0.19

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

hg19: chr20-31024207; API