rs1555744039

Positions:

• chr18-33743919-TGTCTTGATTCCCCC-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_030632.3(ASXL3):​c.4072_4085del​(p.Val1358AsnfsTer4) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASXL3 NM_030632.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.50

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 Likely_pathogenic. Variant got 8 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 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-33743919-TGTCTTGATTCCCCC-T is Pathogenic according to our data. Variant chr18-33743919-TGTCTTGATTCCCCC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 547900.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASXL3	NM_030632.3	c.4072_4085del	p.Val1358AsnfsTer4	frameshift_variant	12/12	ENST00000269197.12	NP_085135.1
LOC124904347	XR_007066447.1	n.84+45_84+58del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASXL3	ENST00000269197.12	c.4072_4085del	p.Val1358AsnfsTer4	frameshift_variant	12/12	5	NM_030632.3	ENSP00000269197	P4
ASXL3	ENST00000681521.1	c.3952_3965del	p.Val1318AsnfsTer4	frameshift_variant	11/11			ENSP00000506037	A2
ASXL3	ENST00000696964.1	c.4075_4088del	p.Val1359AsnfsTer4	frameshift_variant	13/13			ENSP00000513003	A2

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: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	Jun 22, 2018	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-06-22 and interpreted as Likely Pathogenic. Variant was initially reported on 2016-12-15 by GTR ID of laboratory name 500068. The reporting laboratory might also submit to ClinVar. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2016	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555744039; hg19: chr18-31323883;