20-32358776-A-C

Variant names:

• chr20-32358776-A-C
• NM_015338.6:c.1A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_015338.6(ASXL1):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000169 in 1,186,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: ASXL1 NM_015338.6 initiator_codon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

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 Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 29 codons. Genomic position: 32366411. Lost 0.018 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASXL1	NM_015338.6	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 13	ENST00000375687.10	NP_056153.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASXL1	ENST00000375687.10	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 13	5	NM_015338.6	ENSP00000364839.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000169 AC: 2 AN: 1186718 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 583718

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000563

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000105

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 23, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Initiation codon variant in a gene for which loss of function is a known mechanism of disease; however an alternative Methionine exists downstream and the actual effect of this variant on protein function is unknown in the absence of functional studies; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Benign	0.17	T;T;T;T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.90	.;D;D;.;.
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-1.1	N;N;.;.;.
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;D
Polyphen		0.019	B;.;B;.;B
Vest4		0.63
MutPred		1.0		Loss of methylation at K4 (P = 0.0536);Loss of methylation at K4 (P = 0.0536);Loss of methylation at K4 (P = 0.0536);Loss of methylation at K4 (P = 0.0536);Loss of methylation at K4 (P = 0.0536);
MVP		0.30
ClinPred		0.94	D
GERP RS		0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.33
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-30946579;