rs1131691668

Positions:

• chr18-33742954-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.3106C>T​(p.Arg1036Ter) 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ASXL3 NM_030632.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 2.02

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 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-33742954-C-T is Pathogenic according to our data. Variant chr18-33742954-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 429913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-33742954-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASXL3	NM_030632.3	c.3106C>T	p.Arg1036Ter	stop_gained	12/12	ENST00000269197.12	NP_085135.1
LOC124904347	XR_007066447.1	n.421G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASXL3	ENST00000269197.12	c.3106C>T	p.Arg1036Ter	stop_gained	12/12	5	NM_030632.3	ENSP00000269197	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461556 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727062

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 17, 2019	The ASXL3 c.3106C>T (p.Arg1036Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. This variant has been previously reported in four individuals with Bainbridge-Ropers syndrome, including a sibling pair (Kuechler et al. 2017; Koboldt et al. 2018; Myers et al. 2018). In two cases, the p.Arg1036Ter variant is described as occurring de novo (Kuechler et al. 2017; Myers et al. 2018) and, in the family with two affected children, recurrence was attributed to presumed germline mosaicism as both parents were unaffected and did not carry the variant (Koboldt et al. 2018). The p.Arg1036Ter variant is not found in the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Based on the predicted truncating nature of the variant, its rarity, and identification in a de novo state, the p.Arg1036Ter variant is classified as pathogenic for Bainbridge-Ropers syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	May 26, 2021	ACMG classification criteria: PVS1 strong, PS4 moderate, PM2 moderate, PM6 moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics Laboratory - UDIAT Centre Diagnòstic, Hospital Universitari Parc Tauli	Jul 10, 2019	- -
Pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	Aug 06, 2018	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-08-06 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University	May 13, 2021	- -
Pathogenic, criteria provided, single submitter	research	Institute for Genomic Medicine, Nationwide Children's Hospital	Sep 29, 2017	The p.R1036X variant is predicted to cause loss of function as it introduces a stop codon at amino acid 1036, truncating the protein to 46% of its wild-type length. It is not observed in 122,882 individuals of various ancestries in the gnomAD database, indicating it is not a common benign variant in those populations. It has been previously reported as a likely pathogenic variant, though the patient phenotype was not provided. We interpret p.R1036X as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Nov 29, 2023	The ASXL3 c.3106C>T (p.Arg1036Ter) variant has been reported in at least five individuals affected with Bainbridge-Ropers syndrome and the variant occurred de novo in at least four of these individuals, including an instance of possible parental germline mosaicism (Koboldt DC et al., PMID: 29305346; Kuechler A et al., PMID: 2790104; Myers KA et al., PMID: 29367179; Schirwani S et al., PMID: 34436830). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by ten submitters. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a premature termination codon; however, because this occurs in the last exon, this is not predicted to lead to nonsense mediated decay but is predicted to delete >40% of the total protein. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	Nov 07, 2017	- -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jun 17, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2022	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 1213 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31332282, 34653234, 34436830, 29367179, 27901041, 29305346, 27824329, 25363760, 28191890, 28714951, 31981491, 33751541, 32565546, 28191889, 33004838, 34015165) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 26, 2020	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with clinical features of Bainbridge-Ropers syndrome (PMID: 27901041, 29305346, 29367179, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 429913). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the ASXL3 gene (p.Arg1036*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1213 amino acids of the ASXL3 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	D
Vest4		0.073
GERP RS		3.9

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: rs1131691668; hg19: chr18-31322918; COSMIC: COSV52482211;