rs62206933

Variant names:

• chr20-32435697-C-T
• rs62206933
• NM_015338.6:c.2985C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0210
• Publications: 10 publications found

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

ACMG classification

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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.: 32

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

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.: 31 AF XY: 0.00996 AC XY: 7241 AN XY: 727240

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: 49 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

GnomAD4 genome AF: 0.0244 AC: 3723 AN: 152286 Hom.: 123 Cov.: 32 AF XY: 0.0256 AC XY: 1907 AN XY: 74460

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: 35 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: 7 AN: 10616

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00322 AC: 219 AN: 68026

Other (OTH) AF: 0.0260 AC: 55 AN: 2114

Alfa AF: 0.0121 Hom.: 28

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

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Bohring-Opitz syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.8
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)

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

Other links and lift over

dbSNP: rs62206933; hg19: chr20-31023500; COSMIC: COSV60108046; COSMIC: COSV60108046;