chr20-32358793-G-C

Position:

• chr20-32358793-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015338.6(ASXL1):​c.18G>C​(p.Lys6Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. K6K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ASXL1 NM_015338.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.201

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14133102).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASXL1	NM_015338.6	c.18G>C	p.Lys6Asn	missense_variant	1/13	ENST00000375687.10
ASXL1	NM_001164603.1	c.18G>C	p.Lys6Asn	missense_variant	1/5
ASXL1	XM_006723727.4	c.18G>C	p.Lys6Asn	missense_variant	1/12
ASXL1	XM_047439945.1	c.18G>C	p.Lys6Asn	missense_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL1	ENST00000375687.10	c.18G>C	p.Lys6Asn	missense_variant	1/13	5	NM_015338.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2024

The c.18G>C (p.K6N) alteration is located in exon 1 (coding exon 1) of the ASXL1 gene. This alteration results from a G to C substitution at nucleotide position 18, causing the lysine (K) at amino acid position 6 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T;T;T;T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.87	.;D;D;.;.
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.;L;.;L
MutationTaster	Benign	0.99	N;N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.1	N;N;.;.;.
REVEL	Benign	0.12
Sift	Uncertain	0.0030	D;D;.;.;.
Sift4G	Uncertain	0.026	D;D;D;.;D
Polyphen		0.97	D;.;D;.;D
Vest4		0.20
MutPred		0.19		Loss of methylation at K6 (P = 0.0152);Loss of methylation at K6 (P = 0.0152);Loss of methylation at K6 (P = 0.0152);Loss of methylation at K6 (P = 0.0152);Loss of methylation at K6 (P = 0.0152);
MVP		0.41
MPC		1.3
ClinPred		0.78	D
GERP RS		0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.89

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: chr20-30946596;