NM_015338.6:c.1A>C

Variant names:

• chr20-32358776-A-C
• rs2122754733
• NM_015338.6:c.1A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate 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
• 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 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. 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

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.1A>C	p.Met1?	initiator_codon	Exon 1 of 13	NP_056153.2
	ASXL1	NM_001164603.1		c.1A>C	p.Met1?	initiator_codon	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.1A>C	p.Met1?	initiator_codon	Exon 1 of 13	ENSP00000364839.4	Q8IXJ9-1
	ASXL1	ENST00000905973.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 12	ENSP00000576032.1
	ASXL1	ENST00000915088.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 11	ENSP00000585147.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22604

American (AMR) AF: 0.00 AC: 0 AN: 27100

Ashkenazi Jewish (ASJ) AF: 0.0000563 AC: 1 AN: 17748

East Asian (EAS) AF: 0.00 AC: 0 AN: 16888

South Asian (SAS) AF: 0.00 AC: 0 AN: 73868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3810

European-Non Finnish (NFE) AF: 0.00000105 AC: 1 AN: 949204

Other (OTH) AF: 0.00 AC: 0 AN: 44758

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

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_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-1.1	T
PhyloP100		1.6
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.019	B
Vest4		0.63
MutPred		1.0		Loss of methylation at K4 (P = 0.0536)
MVP		0.30
ClinPred		0.94	D
GERP RS		0.13
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.33
gMVP		0.64
Mutation Taster		=16/184	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

Other links and lift over

dbSNP: rs2122754733; hg19: chr20-30946579;