rs200723688

chr18-33743198-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_030632.3(ASXL3):c.3350G>A(p.Arg1117Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000178 in 1,613,914 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: ASXL3 NM_030632.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.72

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2126365).
• BP6: Variant 18-33743198-G-A is Benign according to our data. Variant chr18-33743198-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000188 (275/1461680) while in subpopulation NFE AF= 0.000235 (261/1111864). AF 95% confidence interval is 0.000211. There are 0 homozygotes in gnomad4_exome. There are 130 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASXL3	NM_030632.3	c.3350G>A	p.Arg1117Gln	missense_variant	12/12	ENST00000269197.12
LOC124904347	XR_007066447.1	n.177C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL3	ENST00000269197.12	c.3350G>A	p.Arg1117Gln	missense_variant	12/12	5	NM_030632.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000723 AC: 18 AN: 248958 Hom.: 0 AF XY: 0.0000740 AC XY: 10 AN XY: 135114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000188 AC: 275 AN: 1461680 Hom.: 0 Cov.: 33 AF XY: 0.000179 AC XY: 130 AN XY: 727120

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000235

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74454

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.0000869

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000363 AC: 3

ExAC AF: 0.0000827 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 02, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ASXL3: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.020
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.97	L;.
MutationTaster	Benign	0.64	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.19
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.029	D;.
Polyphen		1.0	D;.
Vest4		0.45
MVP		0.71
MPC		0.52
ClinPred		0.30	T
GERP RS		5.9
Varity_R		0.20
gMVP		0.45

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: rs200723688; hg19: chr18-31323162;