rs75887545

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015338.6(ASXL1):c.3498C>G(p.Ser1166Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,614,224 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0067 ( 15 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 10 hom. )

Consequence

ASXL1
NM_015338.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: -0.0210

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

Bohring-Opitz syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Laboratory for Molecular Medicine, G2P, Illumina

ASXL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028540194).

BP6

Variant 20-32436210-C-G is Benign according to our data. Variant chr20-32436210-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00668 (1017/152340) while in subpopulation AFR AF = 0.0228 (947/41574). AF 95% confidence interval is 0.0216. There are 15 homozygotes in GnomAd4. There are 498 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1017 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015338.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL1	NM_015338.6	MANE Select	c.3498C>G	p.Ser1166Arg	missense	Exon 13 of 13	NP_056153.2
	ASXL1	NM_001363734.1		c.3315C>G	p.Ser1105Arg	missense	Exon 12 of 12	NP_001350663.1	A0A2R8Y5U1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ASXL1	ENST00000375687.10	TSL:5 MANE Select	c.3498C>G	p.Ser1166Arg	missense	Exon 13 of 13	ENSP00000364839.4	Q8IXJ9-1
ASXL1	ENST00000306058.9	TSL:1	c.3483C>G	p.Ser1161Arg	missense	Exon 12 of 12	ENSP00000305119.5	Q76L82
ASXL1	ENST00000905973.1		c.3495C>G	p.Ser1165Arg	missense	Exon 12 of 12	ENSP00000576032.1

Frequencies

GnomAD3 genomes

AF:

0.00668

AC:

1017

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0228

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00347

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00178

AC:

446

AN:

251262

AF XY:

0.00141

show subpopulations

Gnomad AFR exome

AF:

0.0249

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000668

AC:

976

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000606

AC XY:

441

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0229

AC:

768

AN:

33480

American (AMR)

AF:

0.00123

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000486

AC:

AN:

1112012

Other (OTH)

AF:

0.00151

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

153

230

306

383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00668

AC:

1017

AN:

152340

Hom.:

Cov.:

AF XY:

0.00669

AC XY:

498

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0228

AC:

947

AN:

41574

American (AMR)

AF:

0.00346

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68038

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

107

161

214

268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000989

Hom.:

Bravo

AF:

0.00766

ESP6500AA

AF:

0.0256

AC:

113

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00220

AC:

267

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Bohring-Opitz syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.67

CADD

Benign

8.0

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.058

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0029

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

PhyloP100

-0.021

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.70

REVEL

Benign

0.070

Sift

Benign

0.13

Sift4G

Benign

0.67

Polyphen

0.78

Vest4

0.24

MutPred

0.20

Loss of phosphorylation at S1166 (P = 0.0086)

MVP

0.33

MPC

0.16

ClinPred

0.0047

GERP RS

1.2

Varity_R

0.036

gMVP

0.21

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over