rs146464648

Variant names:

• chr20-32436901-G-A
• rs146464648
• NM_015338.6:c.4189G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-32436901-G-A
• chr20-32436901-G-C

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.4189G>A​(p.Gly1397Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,614,200 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1397A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (11 hom.)
• Consequence: ASXL1 NM_015338.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 8.14
• Publications: 19 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=0.0074142218).
• BP6: Variant 20-32436901-G-A is Benign according to our data. Variant chr20-32436901-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00149 (227/152326) while in subpopulation SAS AF = 0.00913 (44/4818). AF 95% confidence interval is 0.00699. There are 1 homozygotes in GnomAd4. There are 115 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 227 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.4189G>A	p.Gly1397Ser	missense	Exon 13 of 13	NP_056153.2
	ASXL1	NM_001363734.1		c.4006G>A	p.Gly1336Ser	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.4189G>A	p.Gly1397Ser	missense	Exon 13 of 13	ENSP00000364839.4	Q8IXJ9-1
	ASXL1	ENST00000306058.9	TSL:1	c.4174G>A	p.Gly1392Ser	missense	Exon 12 of 12	ENSP00000305119.5	Q76L82
	ASXL1	ENST00000905973.1		c.4186G>A	p.Gly1396Ser	missense	Exon 12 of 12	ENSP00000576032.1

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 226 AN: 152208 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00912

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00201 AC: 506 AN: 251464 AF XY: 0.00246

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00185

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00181 AC: 2640 AN: 1461874 Hom.: 11 Cov.: 41 AF XY: 0.00204 AC XY: 1480 AN XY: 727238

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.00116 AC: 52 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00333 AC: 87 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00735 AC: 634 AN: 86258

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53400

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5768

European-Non Finnish (NFE) AF: 0.00156 AC: 1731 AN: 1112012

Other (OTH) AF: 0.00154 AC: 93 AN: 60396

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152326 Hom.: 1 Cov.: 32 AF XY: 0.00154 AC XY: 115 AN XY: 74484

African (AFR) AF: 0.000144 AC: 6 AN: 41576

American (AMR) AF: 0.00202 AC: 31 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00913 AC: 44 AN: 4818

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00168 AC: 114 AN: 68026

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00174 Hom.: 1

Bravo AF: 0.00132

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00207 AC: 251

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00261

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	ASXL1-related disorder (1)
-	-	1	Bohring-Opitz syndrome (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		8.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.11
Sift	Benign	0.043	D
Sift4G	Benign	0.42	T
Polyphen		0.79	P
Vest4		0.12
MVP		0.45
MPC		0.086
ClinPred		0.038	T
GERP RS		4.7
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.12
gMVP		0.25
Mutation Taster		=97/3	polymorphism

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: rs146464648; hg19: chr20-31024704; COSMIC: COSV60104786; COSMIC: COSV60104786;