rs201072457

Positions:

chr18-33745021-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_030632.3(ASXL3):c.5173G>A(p.Asp1725Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000159 in 1,613,986 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 2 hom. )

Consequence

ASXL3
NM_030632.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.63

Variant links:

Genes affected

ASXL3 (HGNC:29357): (ASXL transcriptional regulator 3) This gene encodes a protein containing a plant homeodomain (PHD) zinc finger domain that plays a role in the regulation of gene transcription. The encoded protein has been shown to negatively regulate lipogenesis by binding to and inhibiting the transcriptional activity of two nuclear hormone receptors, oxysterols receptor LXR-alpha (LXRalpha) and thyroid hormone receptor beta (TRbeta). The encoded protein may also inhibit histone deubiquitination. Mutations in this gene have been identified in human patients with Bainbridge-Ropers syndrome, which is characterized by feeding difficulties, developmental delay and other features. [provided by RefSeq, May 2017]

ASXL3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0696747).

BP6

Variant 18-33745021-G-A is Benign according to our data. Variant chr18-33745021-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 434424.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 = 0.000125 (19/152296) while in subpopulation SAS AF= 0.000623 (3/4816). AF 95% confidence interval is 0.000169. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASXL3	NM_030632.3 linkuse as main transcript	c.5173G>A	p.Asp1725Asn	missense_variant	12/12	ENST00000269197.12	NP_085135.1	Q9C0F0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ASXL3	ENST00000269197.12 linkuse as main transcript	c.5173G>A	p.Asp1725Asn	missense_variant	12/12	5	NM_030632.3	ENSP00000269197.4	Q9C0F0-1
ASXL3	ENST00000696964.1 linkuse as main transcript	c.5176G>A	p.Asp1726Asn	missense_variant	13/13			ENSP00000513003.1	A0A8V8TKV8
ASXL3	ENST00000681521.1 linkuse as main transcript	c.5053G>A	p.Asp1685Asn	missense_variant	11/11			ENSP00000506037.1	A0A7P0TAE5

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000197

AC:

AN:

249164

Hom.:

AF XY:

0.000252

AC XY:

AN XY:

135172

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.000279

Gnomad NFE exome

AF:

0.000151

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000162

AC:

237

AN:

1461690

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

150

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000696

Gnomad4 FIN exome

AF:

0.000431

Gnomad4 NFE exome

AF:

0.0000962

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000125

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000172

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000238

AC:

ExAC

AF:

0.000231

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 21, 2019

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ASXL3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 22, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 02, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.032

Eigen

Benign

0.13

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.013

MetaRNN

Benign

0.070

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.92

REVEL

Benign

0.16

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.016

Polyphen

0.91

Vest4

0.081

MVP

0.22

MPC

0.44

ClinPred

0.055

GERP RS

5.9

Varity_R

0.13

gMVP

0.37

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over