dbSNP rs542568224: ASXL1:p.Ser1212Cys (chr20-32436347-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_015338.6(ASXL1):c.3635C>G(p.Ser1212Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. S1212F) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ASXL1
NM_015338.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.53

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-32436347-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.09316644).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASXL1	NM_015338.6 link	c.3635C>G	p.Ser1212Cys	missense_variant	Exon 13 of 13	ENST00000375687.10	NP_056153.2	Q8IXJ9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASXL1	ENST00000375687.10 link	c.3635C>G	p.Ser1212Cys	missense_variant	Exon 13 of 13	5	NM_015338.6	ENSP00000364839.4		Q8IXJ9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461488

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727034

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

9.0

DANN

Uncertain

0.98

DEOGEN2

Benign

0.083

T;T;T;.;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.77

.;T;.;T;T

M_CAP

Benign

0.0020

MetaRNN

Benign

0.093

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;M;M;.;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.0

N;.;.;.;N

REVEL

Benign

0.077

Sift

Benign

0.14

T;.;.;.;T

Sift4G

Benign

0.14

T;T;T;.;T

Polyphen

0.062

B;B;B;.;.

Vest4

0.26

MutPred

0.20

Loss of phosphorylation at S1212 (P = 0.0738);Loss of phosphorylation at S1212 (P = 0.0738);Loss of phosphorylation at S1212 (P = 0.0738);.;.;

MVP

0.25

MPC

0.059

ClinPred

0.61

GERP RS

4.6

Varity_R

0.092

gMVP

0.32

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

Computational scores

Splicing

Publications

Other links and lift over