chr20-32358494-C-T

Variant names:

• chr20-32358494-C-T
• rs530763476
• NM_015338.6:c.-282C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_015338.6(ASXL1):​c.-282C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00887 in 230,060 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0093 (12 hom., cov: 31)
  • Exomes 𝑓: 0.0081 (10 hom.)
• Consequence: ASXL1 NM_015338.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.560
• Publications: 1 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: Illumina, Laboratory for Molecular Medicine, Orphanet, G2P, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 20-32358494-C-T is Benign according to our data. Variant chr20-32358494-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 338062.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00927 (1397/150782) while in subpopulation NFE AF = 0.0115 (775/67564). AF 95% confidence interval is 0.0108. There are 12 homozygotes in GnomAd4. There are 729 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1397 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.-282C>T		5_prime_UTR	Exon 1 of 13	NP_056153.2
	ASXL1	NM_001164603.1		c.-282C>T		5_prime_UTR	Exon 1 of 5	NP_001158075.1	Q498B9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL1	ENST00000375687.10	TSL:5 MANE Select	c.-282C>T		5_prime_UTR	Exon 1 of 13	ENSP00000364839.4	Q8IXJ9-1
	ASXL1	ENST00000905973.1		c.-282C>T		5_prime_UTR	Exon 1 of 12	ENSP00000576032.1
	ASXL1	ENST00000915088.1		c.-282C>T		5_prime_UTR	Exon 1 of 11	ENSP00000585147.1

Frequencies

GnomAD3 genomes AF: 0.00927 AC: 1396 AN: 150674 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00936

Gnomad ASJ AF: 0.00665

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0346

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.0102

GnomAD4 exome AF: 0.00812 AC: 644 AN: 79278 Hom.: 10 Cov.: 0 AF XY: 0.00796 AC XY: 291 AN XY: 36562

African (AFR) AF: 0.00187 AC: 7 AN: 3736

American (AMR) AF: 0.00950 AC: 23 AN: 2422

Ashkenazi Jewish (ASJ) AF: 0.00381 AC: 19 AN: 4992

East Asian (EAS) AF: 0.00 AC: 0 AN: 11294

South Asian (SAS) AF: 0.00399 AC: 4 AN: 1002

European-Finnish (FIN) AF: 0.0357 AC: 5 AN: 140

Middle Eastern (MID) AF: 0.0126 AC: 6 AN: 478

European-Non Finnish (NFE) AF: 0.0108 AC: 524 AN: 48632

Other (OTH) AF: 0.00851 AC: 56 AN: 6582

GnomAD4 genome AF: 0.00927 AC: 1397 AN: 150782 Hom.: 12 Cov.: 31 AF XY: 0.00990 AC XY: 729 AN XY: 73650

African (AFR) AF: 0.00155 AC: 64 AN: 41410

American (AMR) AF: 0.00935 AC: 142 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00665 AC: 23 AN: 3458

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5148

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4830

European-Finnish (FIN) AF: 0.0346 AC: 342 AN: 9896

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0115 AC: 775 AN: 67564

Other (OTH) AF: 0.0101 AC: 21 AN: 2082

Alfa AF: 0.0123 Hom.: 3

Bravo AF: 0.00721

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.95
PhyloP100		0.56
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Mutation Taster		=298/2	polymorphism

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: rs530763476; hg19: chr20-30946297;