18-33740369-C-G

Position:

chr18-33740369-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_030632.3(ASXL3):c.2965C>G(p.Arg989Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,609,562 control chromosomes in the GnomAD database, including 11 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 9 hom. )

Consequence

ASXL3
NM_030632.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.48

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010617167).

BP6

Variant 18-33740369-C-G is Benign according to our data. Variant chr18-33740369-C-G is described in ClinVar as [Benign]. Clinvar id is 389938.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 = 0.0012 (183/152194) while in subpopulation NFE AF= 0.0019 (129/68008). AF 95% confidence interval is 0.00163. There are 2 homozygotes in gnomad4. There are 86 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 183 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASXL3	NM_030632.3 linkuse as main transcript	c.2965C>G	p.Arg989Gly	missense_variant	11/12	ENST00000269197.12	NP_085135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASXL3	ENST00000269197.12 linkuse as main transcript	c.2965C>G	p.Arg989Gly	missense_variant	11/12	5	NM_030632.3	ENSP00000269197	P4	Q9C0F0-1

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

186

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00191

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00119

AC:

288

AN:

241826

Hom.:

AF XY:

0.00119

AC XY:

156

AN XY:

131090

show subpopulations

Gnomad AFR exome

AF:

0.000403

Gnomad AMR exome

AF:

0.00137

Gnomad ASJ exome

AF:

0.000824

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000506

Gnomad FIN exome

AF:

0.000141

Gnomad NFE exome

AF:

0.00189

Gnomad OTH exome

AF:

0.000515

GnomAD4 exome

AF:

0.00188

AC:

2746

AN:

1457368

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

1368

AN XY:

724682

show subpopulations

Gnomad4 AFR exome

AF:

0.000331

Gnomad4 AMR exome

AF:

0.00139

Gnomad4 ASJ exome

AF:

0.00170

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000573

Gnomad4 FIN exome

AF:

0.000319

Gnomad4 NFE exome

AF:

0.00221

Gnomad4 OTH exome

AF:

0.00170

GnomAD4 genome

AF:

0.00120

AC:

183

AN:

152194

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.000866

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00190

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00133

Hom.:

Bravo

AF:

0.00119

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00219

AC:

ExAC

AF:

0.00137

AC:

166

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2019	This variant is associated with the following publications: (PMID: 28785287) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	ASXL3: BP4, BS1, BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 22, 2016

- -

ASXL3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2022

This variant is classified as 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

0.13

Eigen_PC

Benign

0.072

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.0

L;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.5

D;.

REVEL

Benign

0.23

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0040

D;.

Polyphen

0.95

P;.

Vest4

0.91

MVP

0.70

MPC

0.15

ClinPred

0.045

GERP RS

5.0

Varity_R

0.20

gMVP

0.39

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