18-33607742-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_030632.3(ASXL3):c.137+66G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,198,630 control chromosomes in the GnomAD database, including 14,583 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3162 hom., cov: 32)
  • Exomes 𝑓: 0.14 (11421 hom.)
• Consequence: ASXL3 NM_030632.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.402

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 18-33607742-G-A is Benign according to our data. Variant chr18-33607742-G-A is described in ClinVar as [Benign]. Clinvar id is 1273037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASXL3	NM_030632.3	c.137+66G>A		intron_variant		ENST00000269197.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL3	ENST00000269197.12	c.137+66G>A		intron_variant		5	NM_030632.3	P4

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28270 AN: 151722 Hom.: 3152 Cov.: 32

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.170

GnomAD4 exome AF: 0.143 AC: 149784 AN: 1046790 Hom.: 11421 AF XY: 0.142 AC XY: 75218 AN XY: 530274

Gnomad4 AFR exome AF: 0.319

Gnomad4 AMR exome AF: 0.149

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.167

Gnomad4 SAS exome AF: 0.123

Gnomad4 FIN exome AF: 0.120

Gnomad4 NFE exome AF: 0.138

Gnomad4 OTH exome AF: 0.153

GnomAD4 genome AF: 0.186 AC: 28318 AN: 151840 Hom.: 3162 Cov.: 32 AF XY: 0.184 AC XY: 13671 AN XY: 74196

Gnomad4 AFR AF: 0.310

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.169

Gnomad4 EAS AF: 0.133

Gnomad4 SAS AF: 0.121

Gnomad4 FIN AF: 0.125

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.168

Alfa AF: 0.140 Hom.: 2736

Bravo AF: 0.196

Asia WGS AF: 0.139 AC: 487 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	2.2
Dann	Benign	0.38

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: rs4799350; hg19: chr18-31187706;