rs143594454

chr20-32435107-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015338.6(ASXL1):c.2395G>T(p.Asp799Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000989 in 1,613,990 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (4 hom.)
• Consequence: ASXL1 NM_015338.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 1.01

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031474829).
• BP6: Variant 20-32435107-G-T is Benign according to our data. Variant chr20-32435107-G-T is described in ClinVar as [Benign]. Clinvar id is 133594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32435107-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00523 (796/152296) while in subpopulation AFR AF= 0.0185 (767/41542). AF 95% confidence interval is 0.0174. There are 5 homozygotes in gnomad4. There are 357 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 795 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASXL1	NM_015338.6	c.2395G>T	p.Asp799Tyr	missense_variant	13/13	ENST00000375687.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL1	ENST00000375687.10	c.2395G>T	p.Asp799Tyr	missense_variant	13/13	5	NM_015338.6	P1

Frequencies

GnomAD3 genomes AF: 0.00522 AC: 795 AN: 152178 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00132 AC: 329 AN: 250002 Hom.: 1 AF XY: 0.000880 AC XY: 119 AN XY: 135208

Gnomad AFR exome AF: 0.0188

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000548 AC: 801 AN: 1461694 Hom.: 4 Cov.: 30 AF XY: 0.000437 AC XY: 318 AN XY: 727128

Gnomad4 AFR exome AF: 0.0198

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00523 AC: 796 AN: 152296 Hom.: 5 Cov.: 32 AF XY: 0.00479 AC XY: 357 AN XY: 74464

Gnomad4 AFR AF: 0.0185

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00107 Hom.: 1

Bravo AF: 0.00624

ESP6500AA AF: 0.0182 AC: 80

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00165 AC: 200

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 31, 2017	- -

Bohring-Opitz syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.078	T;T;T;.;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.20	N
MetaRNN	Benign	0.0031	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;L;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	N;.;.;.;N
REVEL	Benign	0.037
Sift	Uncertain	0.0030	D;.;.;.;D
Sift4G	Uncertain	0.051	T;T;T;.;T
Polyphen		0.79	P;P;P;.;.
Vest4		0.20
MVP		0.38
MPC		0.27
ClinPred		0.012	T
GERP RS		2.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.043
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs143594454; hg19: chr20-31022910; COSMIC: COSV60123367; COSMIC: COSV60123367;