rs868044680

Variant names:

• chr18-33743197-C-G
• rs868044680
• NM_030632.3:c.3349C>G

Your query was ambiguous. Multiple possible variants found:

• chr18-33743197-C-G
• chr18-33743197-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030632.3(ASXL3):​c.3349C>G​(p.Arg1117Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1117Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ASXL3 NM_030632.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.272
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Illumina, Orphanet, G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

LOC124904347 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20507461).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASXL3	NM_030632.3	c.3349C>G	p.Arg1117Gly	missense_variant	Exon 12 of 12	ENST00000269197.12	NP_085135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASXL3	ENST00000269197.12	c.3349C>G	p.Arg1117Gly	missense_variant	Exon 12 of 12	5	NM_030632.3	ENSP00000269197.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461690 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727122

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111866

Other (OTH) AF: 0.00 AC: 0 AN: 60374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.97	L;.
PhyloP100		0.27
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N;.
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0090	D;.
Polyphen		0.99	D;.
Vest4		0.64
MutPred		0.22		Loss of solvent accessibility (P = 0.0023);.;
MVP		0.82
MPC		0.55
ClinPred		0.93	D
GERP RS		1.5
Varity_R		0.19
gMVP		0.54
Mutation Taster		=80/20	polymorphism

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: rs868044680; hg19: chr18-31323161;