20-32358494-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 1396 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASXL1	NM_015338.6	c.-282C>T		5_prime_UTR_variant	1/13	ENST00000375687.10
ASXL1	NM_001164603.1	c.-282C>T		5_prime_UTR_variant	1/5
ASXL1	XM_006723727.4	c.-282C>T		5_prime_UTR_variant	1/12
ASXL1	XM_047439945.1	c.-282C>T		5_prime_UTR_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL1	ENST00000375687.10	c.-282C>T		5_prime_UTR_variant	1/13	5	NM_015338.6	P1

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

Gnomad4 AFR exome AF: 0.00187

Gnomad4 AMR exome AF: 0.00950

Gnomad4 ASJ exome AF: 0.00381

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00399

Gnomad4 FIN exome AF: 0.0357

Gnomad4 NFE exome AF: 0.0108

Gnomad4 OTH exome AF: 0.00851

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

Gnomad4 AFR AF: 0.00155

Gnomad4 AMR AF: 0.00935

Gnomad4 ASJ AF: 0.00665

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0346

Gnomad4 NFE AF: 0.0115

Gnomad4 OTH AF: 0.0101

Alfa AF: 0.0123 Hom.: 3

Bravo AF: 0.00721

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	18
Dann	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

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

Other links and lift over

dbSNP: rs530763476; hg19: chr20-30946297;