NM_015338.6:c.29A>G

Variant names:

• chr20-32358804-A-G
• NM_015338.6:c.29A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015338.6(ASXL1):​c.29A>G​(p.Glu10Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000767 in 1,303,098 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E10E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: ASXL1 NM_015338.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.00
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10207394).

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.29A>G	p.Glu10Gly	missense	Exon 1 of 13	NP_056153.2
	ASXL1	NM_001164603.1		c.29A>G	p.Glu10Gly	missense	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.29A>G	p.Glu10Gly	missense	Exon 1 of 13	ENSP00000364839.4	Q8IXJ9-1
	ASXL1	ENST00000905973.1		c.29A>G	p.Glu10Gly	missense	Exon 1 of 12	ENSP00000576032.1
	ASXL1	ENST00000915088.1		c.29A>G	p.Glu10Gly	missense	Exon 1 of 11	ENSP00000585147.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.67e-7 AC: 1 AN: 1303098 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 642334

African (AFR) AF: 0.00 AC: 0 AN: 25872

American (AMR) AF: 0.00 AC: 0 AN: 30698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21778

East Asian (EAS) AF: 0.00 AC: 0 AN: 27042

South Asian (SAS) AF: 0.00 AC: 0 AN: 75308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4324

European-Non Finnish (NFE) AF: 9.75e-7 AC: 1 AN: 1026114

Other (OTH) AF: 0.00 AC: 0 AN: 52074

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.075
Eigen_PC	Benign	-0.098
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.32	N
REVEL	Benign	0.074
Sift	Benign	0.10	T
Sift4G	Benign	0.57	T
Polyphen		0.95	P
Vest4		0.19
MutPred		0.18		Loss of methylation at K6 (P = 0.0472)
MVP		0.41
MPC		1.4
ClinPred		0.51	D
GERP RS		1.5
PromoterAI		-0.076	Neutral
Varity_R		0.16
gMVP		0.81
Mutation Taster		=77/23	polymorphism

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

hg19: chr20-30946607;