rs143578678

Positions:

chr18-33744850-G-A

Variant summary

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

The NM_030632.3(ASXL3):c.5002G>A(p.Val1668Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00039 in 1,614,024 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 3 hom. )

Consequence

ASXL3
NM_030632.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.61

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=0.007395923).

BP6

Variant 18-33744850-G-A is Benign according to our data. Variant chr18-33744850-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-33744850-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00202 (307/152326) while in subpopulation AFR AF= 0.00707 (294/41570). AF 95% confidence interval is 0.00641. There are 2 homozygotes in gnomad4. There are 140 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 307 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASXL3	NM_030632.3 linkuse as main transcript	c.5002G>A	p.Val1668Met	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.5002G>A	p.Val1668Met	missense_variant	12/12	5	NM_030632.3	ENSP00000269197.4	Q9C0F0-1
ASXL3	ENST00000696964.1 linkuse as main transcript	c.5005G>A	p.Val1669Met	missense_variant	13/13			ENSP00000513003.1	A0A8V8TKV8
ASXL3	ENST00000681521.1 linkuse as main transcript	c.4882G>A	p.Val1628Met	missense_variant	11/11			ENSP00000506037.1	A0A7P0TAE5

Frequencies

GnomAD3 genomes

AF:

0.00200

AC:

304

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00702

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000574

AC:

143

AN:

249212

Hom.:

AF XY:

0.000436

AC XY:

AN XY:

135208

show subpopulations

Gnomad AFR exome

AF:

0.00756

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000668

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000221

AC:

323

AN:

1461698

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

131

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.00717

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000663

GnomAD4 genome

AF:

0.00202

AC:

307

AN:

152326

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

140

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00707

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000348

Hom.:

Bravo

AF:

0.00226

ESP6500AA

AF:

0.00647

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000670

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 14, 2016	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2023

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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2019

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

0.13

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.055

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.47

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.81

M_CAP

Benign

0.0057

MetaRNN

Benign

0.0074

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.64

REVEL

Benign

0.013

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0050

Polyphen

0.10

Vest4

0.15

MVP

0.068

MPC

0.13

ClinPred

0.034

GERP RS

2.0

Varity_R

0.070

gMVP

0.29

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