rs797045317

Positions:

• chr18-33738591-CACAG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_030632.3(ASXL3):​c.1192_1195del​(p.Thr398ProfsTer10) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASXL3 NM_030632.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.09

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-33738591-CACAG-C is Pathogenic according to our data. Variant chr18-33738591-CACAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 210364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASXL3	NM_030632.3	c.1192_1195del	p.Thr398ProfsTer10	frameshift_variant	11/12	ENST00000269197.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL3	ENST00000269197.12	c.1192_1195del	p.Thr398ProfsTer10	frameshift_variant	11/12	5	NM_030632.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	May 25, 2018	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-05-25 and interpreted as Pathogenic. Variant was initially reported on 2017-03-22 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 16, 2015	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 07, 2019

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016) -

Computational scores

Source: dbNSFP v4.3

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: rs797045317; hg19: chr18-31318555;