rs1365687375

Variant names:

• chr20-32358816-C-T
• rs1365687375
• NM_015338.6:c.41C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_015338.6(ASXL1):​c.41C>T​(p.Ala14Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,336,904 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: ASXL1 NM_015338.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.26
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 20-32358816-C-T is Benign according to our data. Variant chr20-32358816-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1716339.

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.41C>T	p.Ala14Val	missense	Exon 1 of 13	NP_056153.2
	ASXL1	NM_001164603.1		c.41C>T	p.Ala14Val	missense	Exon 1 of 5	NP_001158075.1	Q498B9
	ASXL1	NM_001363734.1		c.-492C>T		upstream_gene	N/A	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.41C>T	p.Ala14Val	missense	Exon 1 of 13	ENSP00000364839.4	Q8IXJ9-1
	ASXL1	ENST00000905973.1		c.41C>T	p.Ala14Val	missense	Exon 1 of 12	ENSP00000576032.1
	ASXL1	ENST00000915088.1		c.41C>T	p.Ala14Val	missense	Exon 1 of 11	ENSP00000585147.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000181 AC: 2 AN: 110640 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000981

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1336904 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 659420

African (AFR) AF: 0.00 AC: 0 AN: 26764

American (AMR) AF: 0.0000638 AC: 2 AN: 31334

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22996

East Asian (EAS) AF: 0.00 AC: 0 AN: 29690

South Asian (SAS) AF: 0.00 AC: 0 AN: 75410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4400

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1047898

Other (OTH) AF: 0.00 AC: 0 AN: 54486

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.00093
Eigen_PC	Benign	-0.034
FATHMM_MKL	Benign	0.47	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.17
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.022	D
Polyphen		0.76	P
Vest4		0.18
MutPred		0.30		Loss of disorder (P = 0.063)
MVP		0.43
MPC		1.0
ClinPred		0.27	T
GERP RS		1.5
PromoterAI		0.0082	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.86
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1365687375; hg19: chr20-30946619;