20-32358851-G-A

Position:

• chr20-32358851-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015338.6(ASXL1):​c.57+19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00839 in 1,504,616 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0087 (65 hom.)
• Consequence: ASXL1 NM_015338.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.31

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 20-32358851-G-A is Benign according to our data. Variant chr20-32358851-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1168641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32358851-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00597 (906/151840) while in subpopulation NFE AF= 0.00951 (645/67856). AF 95% confidence interval is 0.0089. There are 6 homozygotes in gnomad4. There are 412 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 906 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASXL1	NM_015338.6	c.57+19G>A		intron_variant		ENST00000375687.10
ASXL1	NM_001164603.1	c.57+19G>A		intron_variant
ASXL1	XM_006723727.4	c.57+19G>A		intron_variant
ASXL1	XM_047439945.1	c.57+19G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL1	ENST00000375687.10	c.57+19G>A		intron_variant		5	NM_015338.6	P1

Frequencies

GnomAD3 genomes AF: 0.00597 AC: 906 AN: 151734 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.00551

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00515

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00950

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00741 AC: 787 AN: 106206 Hom.: 6 AF XY: 0.00673 AC XY: 395 AN XY: 58722

Gnomad AFR exome AF: 0.00121

Gnomad AMR exome AF: 0.00856

Gnomad ASJ exome AF: 0.00852

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000750

Gnomad FIN exome AF: 0.00605

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.0141

GnomAD4 exome AF: 0.00866 AC: 11711 AN: 1352776 Hom.: 65 Cov.: 33 AF XY: 0.00833 AC XY: 5558 AN XY: 667042

Gnomad4 AFR exome AF: 0.00129

Gnomad4 AMR exome AF: 0.00815

Gnomad4 ASJ exome AF: 0.00890

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000653

Gnomad4 FIN exome AF: 0.00739

Gnomad4 NFE exome AF: 0.00988

Gnomad4 OTH exome AF: 0.00628

GnomAD4 genome AF: 0.00597 AC: 906 AN: 151840 Hom.: 6 Cov.: 31 AF XY: 0.00555 AC XY: 412 AN XY: 74230

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00550

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00515

Gnomad4 NFE AF: 0.00951

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00355 Hom.: 5

Bravo AF: 0.00629

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2018	- -

Bohring-Opitz syndrome;C3463824:Myelodysplastic syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 22, 2021

- -

Bohring-Opitz syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	17
DANN	Benign	0.91

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: rs200198574; hg19: chr20-30946654;