rs868044680

Positions:

• chr18-33743197-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_030632.3(ASXL3):​c.3349C>T​(p.Arg1117*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASXL3 NM_030632.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.272

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]

LOC124904347 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-33743197-C-T is Pathogenic according to our data. Variant chr18-33743197-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 279694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-33743197-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASXL3	NM_030632.3	c.3349C>T	p.Arg1117*	stop_gained	12/12	ENST00000269197.12	NP_085135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASXL3	ENST00000269197.12	c.3349C>T	p.Arg1117*	stop_gained	12/12	5	NM_030632.3	ENSP00000269197.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 01, 2021	The ASXL3 c.3349C>T p.(Arg1117Ter) nonsense variant occurs in the last exon of the gene and the resulting transcript may escape nonsense-mediated mRNA decay. This variant has been identified in individuals with a phenotype consistent with Bainbridge-Ropers syndrome, including in a de novo state in at least one individual (Hedge et al. 2017; Zhang et al. 2018). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. Based on the available evidence, the c.3349C>T p.(Arg1117Ter) variant is classified as likely pathogenic for Bainbridge-Ropers syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Nov 25, 2022	ACMG classification criteria: PVS1 very strong, PS4 supporting, PM2 moderated -
Pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	Nov 30, 2018	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-11-30 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Mar 11, 2024	- -
Pathogenic, no assertion criteria provided	research	Pediatric Department, Xiangya Hospital, Central South University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2019	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 1132 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28362156, 26633542, 29429203, 33258288) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 05, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.57	D
Vest4		0.32
GERP RS		1.5

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

Other links and lift over

dbSNP: rs868044680; hg19: chr18-31323161; COSMIC: COSV52463509;