NM_015338.6:c.2985C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_015338.6(ASXL1):c.2985C>T(p.His995His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,614,160 control chromosomes in the GnomAD database, including 671 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 123 hom., cov: 32)

Exomes 𝑓: 0.010 ( 548 hom. )

Consequence

ASXL1
NM_015338.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0210

Publications

10 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Illumina, ClinGen, Laboratory for Molecular Medicine, G2P, Orphanet

ASXL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 20-32435697-C-T is Benign according to our data. Variant chr20-32435697-C-T is described in ClinVar as Benign. ClinVar VariationId is 338104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.021 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0827 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL1	NM_015338.6	MANE Select	c.2985C>T	p.His995His	synonymous	Exon 13 of 13	NP_056153.2
	ASXL1	NM_001363734.1		c.2802C>T	p.His934His	synonymous	Exon 12 of 12	NP_001350663.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ASXL1	ENST00000375687.10	TSL:5 MANE Select	c.2985C>T	p.His995His	synonymous	Exon 13 of 13	ENSP00000364839.4
ASXL1	ENST00000306058.9	TSL:1	c.2970C>T	p.His990His	synonymous	Exon 12 of 12	ENSP00000305119.5
ASXL1	ENST00000646985.1		c.2802C>T	p.His934His	synonymous	Exon 12 of 12	ENSP00000495053.1

Frequencies

GnomAD3 genomes

AF:

0.0244

AC:

3718

AN:

152168

Hom.:

124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0443

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0865

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.0254

Gnomad SAS

AF:

0.0217

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00322

Gnomad OTH

AF:

0.0263

GnomAD2 exomes

AF:

0.0278

AC:

6982

AN:

251428

AF XY:

0.0231

show subpopulations

Gnomad AFR exome

AF:

0.0445

Gnomad AMR exome

AF:

0.128

Gnomad ASJ exome

AF:

0.0125

Gnomad EAS exome

AF:

0.0246

Gnomad FIN exome

AF:

0.000832

Gnomad NFE exome

AF:

0.00362

Gnomad OTH exome

AF:

0.0200

GnomAD4 exome

AF:

0.0104

AC:

15160

AN:

1461874

Hom.:

548

Cov.:

AF XY:

0.00996

AC XY:

7241

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0465

AC:

1557

AN:

33480

American (AMR)

AF:

0.124

AC:

5564

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

316

AN:

26136

East Asian (EAS)

AF:

0.0366

AC:

1452

AN:

39700

South Asian (SAS)

AF:

0.0197

AC:

1703

AN:

86258

European-Finnish (FIN)

AF:

0.000917

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.0184

AC:

106

AN:

5768

European-Non Finnish (NFE)

AF:

0.00323

AC:

3594

AN:

1112008

Other (OTH)

AF:

0.0136

AC:

819

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1102

2204

3305

4407

5509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

276

552

828

1104

1380

<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:

0.0244

AC:

3723

AN:

152286

Hom.:

123

Cov.:

AF XY:

0.0256

AC XY:

1907

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0443

AC:

1840

AN:

41544

American (AMR)

AF:

0.0865

AC:

1324

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3470

East Asian (EAS)

AF:

0.0255

AC:

132

AN:

5186

South Asian (SAS)

AF:

0.0214

AC:

103

AN:

4824

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00322

AC:

219

AN:

68026

Other (OTH)

AF:

0.0260

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

177

354

531

708

885

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0121

Hom.:

Bravo

AF:

0.0324

Asia WGS

AF:

0.0440

AC:

153

AN:

3478

EpiCase

AF:

0.00431

EpiControl

AF:

0.00498

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Bohring-Opitz syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

5.8

(source)

DANN

Benign

0.45

PhyloP100

-0.021

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over