rs780662350

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_015338.6(ASXL1):​c.664G>A​(p.Glu222Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000023 in 1,608,316 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

ASXL1
NM_015338.6 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.81
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BS2
High AC in GnomAd4 at 10 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ASXL1NM_015338.6 linkuse as main transcriptc.664G>A p.Glu222Lys missense_variant 8/13 ENST00000375687.10 NP_056153.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ASXL1ENST00000375687.10 linkuse as main transcriptc.664G>A p.Glu222Lys missense_variant 8/135 NM_015338.6 ENSP00000364839 P1Q8IXJ9-1

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152228
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000249
AC:
6
AN:
241046
Hom.:
0
AF XY:
0.0000151
AC XY:
2
AN XY:
132146
show subpopulations
Gnomad AFR exome
AF:
0.000200
Gnomad AMR exome
AF:
0.00
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:
0.0000274
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000185
AC:
27
AN:
1456088
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
724650
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000216
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152228
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74382
show subpopulations
Gnomad4 AFR
AF:
0.0000965
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.0000248
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypertonia;C0036572:Seizure;C0454644:Delayed speech and language development;C2237142:Moderate global developmental delay Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter of Genomic medicine, Geneva, University Hospital of GenevaMay 22, 2017- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 21, 2021In 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 missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 433179). This variant has not been reported in the literature in individuals affected with ASXL1-related conditions. This variant is present in population databases (rs780662350, ExAC 0.01%). This sequence change replaces glutamic acid with lysine at codon 222 of the ASXL1 protein (p.Glu222Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. -
Global developmental delay;C1860834:Infantile muscular hypotonia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter of Genomic medicine, Geneva, University Hospital of GenevaMay 22, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.25
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.15
T;T;T;T
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.89
.;D;.;D
M_CAP
Benign
0.0077
T
MetaRNN
Uncertain
0.56
D;D;D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
L;L;L;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-0.88
N;.;.;N
REVEL
Benign
0.17
Sift
Uncertain
0.0050
D;.;.;D
Sift4G
Benign
0.53
T;T;T;T
Polyphen
1.0
D;D;D;.
Vest4
0.70
MVP
0.46
MPC
1.8
ClinPred
0.30
T
GERP RS
4.9
Varity_R
0.32
gMVP
0.48

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs780662350; hg19: chr20-31017802; COSMIC: COSV60116087; COSMIC: COSV60116087; API