18-33686777-A-G

Variant names:

• chr18-33686777-A-G
• rs4799710
• NM_030632.3:c.879+3209A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_030632.3(ASXL3):​c.879+3209A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 152,058 control chromosomes in the GnomAD database, including 25,014 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.57 (25014 hom., cov: 32)
• Consequence: ASXL3 NM_030632.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.632
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Illumina
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030632.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL3	NM_030632.3	MANE Select	c.879+3209A>G		intron	N/A	NP_085135.1	Q9C0F0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL3	ENST00000269197.12	TSL:5 MANE Select	c.879+3209A>G		intron	N/A	ENSP00000269197.4	Q9C0F0-1
	ASXL3	ENST00000696964.1		c.882+3209A>G		intron	N/A	ENSP00000513003.1	A0A8V8TKV8
	ASXL3	ENST00000681521.1		c.759+3209A>G		intron	N/A	ENSP00000506037.1	A0A7P0TAE5

Frequencies

GnomAD3 genomes AF: 0.566 AC: 86001 AN: 151940 Hom.: 24980 Cov.: 32

Gnomad AFR AF: 0.613

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.609

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.900

Gnomad SAS AF: 0.482

Gnomad FIN AF: 0.576

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.516

Gnomad OTH AF: 0.535

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

GnomAD4 genome AF: 0.566 AC: 86091 AN: 152058 Hom.: 25014 Cov.: 32 AF XY: 0.570 AC XY: 42337 AN XY: 74328

African (AFR) AF: 0.613 AC: 25432 AN: 41484

American (AMR) AF: 0.609 AC: 9306 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1440 AN: 3470

East Asian (EAS) AF: 0.900 AC: 4631 AN: 5144

South Asian (SAS) AF: 0.482 AC: 2324 AN: 4820

European-Finnish (FIN) AF: 0.576 AC: 6092 AN: 10572

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.516 AC: 35079 AN: 67980

Other (OTH) AF: 0.537 AC: 1132 AN: 2108

Alfa AF: 0.517 Hom.: 24760

Bravo AF: 0.578

Asia WGS AF: 0.698 AC: 2424 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.3
DANN	Benign	0.54
PhyloP100		0.63
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4799710; hg19: chr18-31266741;