20-32436457-A-G

Variant names:

• chr20-32436457-A-G
• rs146141075
• NM_015338.6:c.3745A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015338.6(ASXL1):​c.3745A>G​(p.Met1249Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,614,152 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1249T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (6 hom.)
• Consequence: ASXL1 NM_015338.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -1.15
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002648145).
• BP6: Variant 20-32436457-A-G is Benign according to our data. Variant chr20-32436457-A-G is described in ClinVar as Benign. ClinVar VariationId is 133580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00198 (302/152358) while in subpopulation NFE AF = 0.00238 (162/68032). AF 95% confidence interval is 0.00208. There are 0 homozygotes in GnomAd4. There are 160 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 302 AD gene.

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.3745A>G	p.Met1249Val	missense	Exon 13 of 13	NP_056153.2
	ASXL1	NM_001363734.1		c.3562A>G	p.Met1188Val	missense	Exon 12 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.3745A>G	p.Met1249Val	missense	Exon 13 of 13	ENSP00000364839.4	Q8IXJ9-1
	ASXL1	ENST00000306058.9	TSL:1	c.3730A>G	p.Met1244Val	missense	Exon 12 of 12	ENSP00000305119.5	Q76L82
	ASXL1	ENST00000905973.1		c.3742A>G	p.Met1248Val	missense	Exon 12 of 12	ENSP00000576032.1

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 302 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00884

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00238

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00220 AC: 553 AN: 251180 AF XY: 0.00219

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.00224

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00220 AC: 3216 AN: 1461794 Hom.: 6 Cov.: 31 AF XY: 0.00221 AC XY: 1606 AN XY: 727204

African (AFR) AF: 0.000657 AC: 22 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000788 AC: 68 AN: 86258

European-Finnish (FIN) AF: 0.0107 AC: 569 AN: 53330

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00218 AC: 2427 AN: 1112008

Other (OTH) AF: 0.00169 AC: 102 AN: 60394

GnomAD4 genome AF: 0.00198 AC: 302 AN: 152358 Hom.: 0 Cov.: 32 AF XY: 0.00215 AC XY: 160 AN XY: 74516

African (AFR) AF: 0.000529 AC: 22 AN: 41578

American (AMR) AF: 0.000588 AC: 9 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4820

European-Finnish (FIN) AF: 0.00884 AC: 94 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00238 AC: 162 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00180 Hom.: 1

Bravo AF: 0.00122

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00198 AC: 241

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	Bohring-Opitz syndrome (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0050
DANN	Benign	0.37
DEOGEN2	Benign	0.019	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-1.1
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.0030
Sift	Benign	0.50	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.0070
MVP		0.061
MPC		0.058
ClinPred		0.0016	T
GERP RS		-8.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.98
Varity_R		0.038
gMVP		0.15
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146141075; hg19: chr20-31024260; COSMIC: COSV60106533; COSMIC: COSV60106533;