rs376997378

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5BS2

The NM_030632.3(ASXL3):c.3136G>A(p.Gly1046Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,566 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

ASXL3
NM_030632.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 9.31

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:

LOC124904347 (HGNC:):

LOC124904347 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP5

Variant 18-33742984-G-A is Pathogenic according to our data. Variant chr18-33742984-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 402202.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}. Variant chr18-33742984-G-A is described in Lovd as [Pathogenic].

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASXL3	NM_030632.3 link	c.3136G>A	p.Gly1046Arg	missense_variant	Exon 12 of 12	ENST00000269197.12	NP_085135.1	Q9C0F0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASXL3	ENST00000269197.12 link	c.3136G>A	p.Gly1046Arg	missense_variant	Exon 12 of 12	5	NM_030632.3	ENSP00000269197.4		Q9C0F0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248448

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000267

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461566

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000595

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:2

Jan 18, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.3136G>Ap.Gly1046Arg in ASXL3 gene has been reported in an individual affected with ASXL3 related disorders. The variant is reported with an allele frequency of 0.002% in the gnomAD exomes database and is novel not in any individuals in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely pathogenic/ Uncertain significance. The amino acid change p.Gly1046Arg in ASXL3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 1046 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. Additional Functional studies are required to prove pathogenicity of the variant. For these reasons, this variant has been classified as Variant of Uncertain significance VUS. -

Abnormal brain morphology

Pathogenic:1

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.013

MetaRNN

Uncertain

0.44

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.97

L;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.35

N;.

REVEL

Benign

0.26

Sift

Benign

0.15

T;.

Sift4G

Benign

0.46

T;.

Polyphen

1.0

D;.

Vest4

0.86

MutPred

0.23

Gain of methylation at G1046 (P = 0.0158);.;

MVP

0.11

MPC

0.57

ClinPred

0.92

GERP RS

5.9

Varity_R

0.19

gMVP

0.55

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