20-32358685-A-ACCG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_015338.6(ASXL1):c.-79_-77dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 501,580 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: ASXL1 NM_015338.6 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.296

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 -9 ACMG points.

• BP6: Variant 20-32358685-A-ACCG is Benign according to our data. Variant chr20-32358685-A-ACCG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 338072.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00377 (490/129994) while in subpopulation AMR AF= 0.0088 (120/13632). AF 95% confidence interval is 0.00752. There are 3 homozygotes in gnomad4. There are 242 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 490 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASXL1	NM_015338.6	c.-79_-77dup		5_prime_UTR_variant	1/13	ENST00000375687.10
ASXL1	NM_001164603.1	c.-79_-77dup		5_prime_UTR_variant	1/5
ASXL1	XM_006723727.4	c.-79_-77dup		5_prime_UTR_variant	1/12
ASXL1	XM_047439945.1	c.-79_-77dup		5_prime_UTR_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL1	ENST00000375687.10	c.-79_-77dup		5_prime_UTR_variant	1/13	5	NM_015338.6	P1

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 490 AN: 129906 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00882

Gnomad ASJ AF: 0.00127

Gnomad EAS AF: 0.000228

Gnomad SAS AF: 0.00384

Gnomad FIN AF: 0.000698

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00499

Gnomad OTH AF: 0.00277

GnomAD4 exome AF: 0.00112 AC: 416 AN: 371586 Hom.: 1 Cov.: 6 AF XY: 0.00111 AC XY: 199 AN XY: 179636

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000745

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000515

Gnomad4 FIN exome AF: 0.000137

Gnomad4 NFE exome AF: 0.00125

Gnomad4 OTH exome AF: 0.000710

GnomAD4 genome AF: 0.00377 AC: 490 AN: 129994 Hom.: 3 Cov.: 31 AF XY: 0.00383 AC XY: 242 AN XY: 63186

Gnomad4 AFR AF: 0.00117

Gnomad4 AMR AF: 0.00880

Gnomad4 ASJ AF: 0.00127

Gnomad4 EAS AF: 0.000228

Gnomad4 SAS AF: 0.00385

Gnomad4 FIN AF: 0.000698

Gnomad4 NFE AF: 0.00499

Gnomad4 OTH AF: 0.00274

Alfa AF: 0.000814 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bohring-Opitz syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

ASXL1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886056593; hg19: chr20-30946488;