18-33578660-G-A

Position:

• chr18-33578660-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030632.3(ASXL3):​c.29G>A​(p.Arg10His) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,207,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: ASXL3 NM_030632.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.16

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1520769).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASXL3	NM_030632.3	c.29G>A	p.Arg10His	missense_variant	1/12	ENST00000269197.12
ASXL3	XM_005258356.2	c.29G>A	p.Arg10His	missense_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL3	ENST00000269197.12	c.29G>A	p.Arg10His	missense_variant	1/12	5	NM_030632.3	P4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000248 AC: 3 AN: 1207554 Hom.: 0 Cov.: 30 AF XY: 0.00000502 AC XY: 3 AN XY: 597578

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000321

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000166

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000104

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000836 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2021

The c.29G>A (p.R10H) alteration is located in exon 1 (coding exon 1) of the ASXL3 gene. This alteration results from a G to A substitution at nucleotide position 29, causing the arginine (R) at amino acid position 10 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.95	N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.12
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0030	B
Vest4		0.47
MutPred		0.28		Loss of MoRF binding (P = 0.0653);
MVP		0.13
MPC		0.14
ClinPred		0.58	D
GERP RS		1.3
Varity_R		0.14
gMVP		0.23

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: rs773417248; hg19: chr18-31158624;