NM_015338.6:c.-4A>G

Variant names:

• chr20-32358772-A-G
• rs771767100
• NM_015338.6:c.-4A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015338.6(ASXL1):​c.-4A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 1,308,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: ASXL1 NM_015338.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.814
• Publications: 0 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Laboratory for Molecular Medicine, G2P, Illumina

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 20-32358772-A-G is Benign according to our data. Variant chr20-32358772-A-G is described in ClinVar as Benign. ClinVar VariationId is 1266577.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00117 (164/140528) while in subpopulation AFR AF = 0.00407 (155/38048). AF 95% confidence interval is 0.00355. There are 0 homozygotes in GnomAd4. There are 79 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 164 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.-4A>G		5_prime_UTR	Exon 1 of 13	NP_056153.2
	ASXL1	NM_001164603.1		c.-4A>G		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.-4A>G		5_prime_UTR	Exon 1 of 13	ENSP00000364839.4	Q8IXJ9-1
	ASXL1	ENST00000905973.1		c.-4A>G		5_prime_UTR	Exon 1 of 12	ENSP00000576032.1
	ASXL1	ENST00000915088.1		c.-4A>G		5_prime_UTR	Exon 1 of 11	ENSP00000585147.1

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 164 AN: 140416 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00409

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000423

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00154

GnomAD2 exomes AF: 0.000128 AC: 14 AN: 109100 AF XY: 0.0000666

Gnomad AFR exome AF: 0.00474

Gnomad AMR exome AF: 0.000150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000123 AC: 144 AN: 1167754 Hom.: 0 Cov.: 28 AF XY: 0.0000975 AC XY: 56 AN XY: 574502

African (AFR) AF: 0.00544 AC: 121 AN: 22258

American (AMR) AF: 0.000228 AC: 6 AN: 26360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17452

East Asian (EAS) AF: 0.00 AC: 0 AN: 16624

South Asian (SAS) AF: 0.0000137 AC: 1 AN: 72868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3650

European-Non Finnish (NFE) AF: 0.00000321 AC: 3 AN: 934204

Other (OTH) AF: 0.000297 AC: 13 AN: 43780

GnomAD4 genome AF: 0.00117 AC: 164 AN: 140528 Hom.: 0 Cov.: 31 AF XY: 0.00116 AC XY: 79 AN XY: 68350

African (AFR) AF: 0.00407 AC: 155 AN: 38048

American (AMR) AF: 0.000422 AC: 6 AN: 14212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 4308

South Asian (SAS) AF: 0.00 AC: 0 AN: 4136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 256

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65152

Other (OTH) AF: 0.00152 AC: 3 AN: 1968

Alfa AF: 0.000419 Hom.: 0

ClinVar

ClinVar submissions

Significance: 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	-0.57
CADD	Benign	19
DANN	Benign	0.88
PhyloP100		0.81
PromoterAI		0.013	Neutral
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

Other links and lift over

dbSNP: rs771767100; hg19: chr20-30946575;