rs143337375

chr20-32369134-T-C

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.252+11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,588,204 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (19 hom.)
• Consequence: ASXL1 NM_015338.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.541

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=-0.75).
• BP6: Variant 20-32369134-T-C is Benign according to our data. Variant chr20-32369134-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 338076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32369134-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0016 (244/152304) while in subpopulation SAS AF= 0.0102 (49/4824). AF 95% confidence interval is 0.00789. There are 0 homozygotes in gnomad4. There are 142 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 244 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASXL1	NM_015338.6	c.252+11T>C		intron_variant		ENST00000375687.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL1	ENST00000375687.10	c.252+11T>C		intron_variant		5	NM_015338.6	P1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 244 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00433

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00251 AC: 631 AN: 251378 Hom.: 6 AF XY: 0.00315 AC XY: 428 AN XY: 135846

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0109

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00183

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00162 AC: 2319 AN: 1435900 Hom.: 19 Cov.: 29 AF XY: 0.00200 AC XY: 1433 AN XY: 715812

Gnomad4 AFR exome AF: 0.000182

Gnomad4 AMR exome AF: 0.00149

Gnomad4 ASJ exome AF: 0.00227

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0105

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.000987

Gnomad4 OTH exome AF: 0.00227

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74484

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00433

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0102

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.00164

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2022

- -

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	-0.75
Cadd	Benign	4.1
Dann	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs143337375; hg19: chr20-30956937;