rs762217973

Positions:

chr18-33738618-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_030632.3(ASXL3):c.1214C>T(p.Pro405Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000607 in 1,613,752 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

ASXL3
NM_030632.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09394604).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASXL3	NM_030632.3 linkuse as main transcript	c.1214C>T	p.Pro405Leu	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.1214C>T	p.Pro405Leu	missense_variant	11/12	5	NM_030632.3	ENSP00000269197	P4	Q9C0F0-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249002

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135090

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000629

AC:

AN:

1461622

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727080

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000747

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.00000828

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	ASXL3: BP4 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 27, 2016

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

The ASXL3 c.1214C>T p.Pro405Leu is a missense variant that changes a single amino acid in the protein coding region from a proline to leucine. This variant has not been reported in the literature and is of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.094

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.5

N;.

REVEL

Benign

0.043

Sift

Benign

0.050

D;.

Sift4G

Uncertain

0.014

D;.

Polyphen

0.037

B;.

Vest4

0.057

MVP

0.11

MPC

0.11

ClinPred

0.12

GERP RS

4.9

Varity_R

0.057

gMVP

0.38

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