rs587778058

Variant names:

• chr20-32432899-G-T
• rs587778058
• NM_015338.6:c.999G>T
• ASXL1 p.Met333Ile

Your query was ambiguous. Multiple possible variants found:

• chr20-32432899-G-T
• chr20-32432899-G-A

Variant summary

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

The NM_015338.6(ASXL1):​c.999G>T​(p.Met333Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M333L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASXL1 NM_015338.6 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.61
• Publications: 2 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), Illumina, Orphanet, Laboratory for Molecular Medicine, ClinGen, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.999G>T	p.Met333Ile	missense	Exon 11 of 13	NP_056153.2
	ASXL1	NM_001363734.1		c.816G>T	p.Met272Ile	missense	Exon 10 of 12	NP_001350663.1	A0A2R8Y5U1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL1	ENST00000375687.10	TSL:5 MANE Select	c.999G>T	p.Met333Ile	missense	Exon 11 of 13	ENSP00000364839.4	Q8IXJ9-1
	ASXL1	ENST00000306058.9	TSL:1	c.984G>T	p.Met328Ile	missense	Exon 10 of 12	ENSP00000305119.5	Q76L82
	ASXL1	ENST00000905973.1		c.996G>T	p.Met332Ile	missense	Exon 10 of 12	ENSP00000576032.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.24
Sift	Uncertain	0.022	D
Sift4G	Benign	0.095	T
Varity_R		0.55
gMVP		0.83
Mutation Taster		=38/62	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs587778058;

hg19: chr20-31020702;