rs189786599

Variant names:

• chr18-33739329-C-T
• rs189786599
• NM_030632.3:c.1925C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_030632.3(ASXL3):​c.1925C>T​(p.Pro642Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000242 in 1,613,512 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P642S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (7 hom.)
• Consequence: ASXL3 NM_030632.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 5.19
• Publications: 2 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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068764687).
• BP6: Variant 18-33739329-C-T is Benign according to our data. Variant chr18-33739329-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210368.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000374 (57/152332) while in subpopulation EAS AF = 0.00771 (40/5186). AF 95% confidence interval is 0.00582. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 57 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL3	NM_030632.3	MANE Select	c.1925C>T	p.Pro642Leu	missense	Exon 11 of 12	NP_085135.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL3	ENST00000269197.12	TSL:5 MANE Select	c.1925C>T	p.Pro642Leu	missense	Exon 11 of 12	ENSP00000269197.4
	ASXL3	ENST00000696964.1		c.1928C>T	p.Pro643Leu	missense	Exon 12 of 13	ENSP00000513003.1
	ASXL3	ENST00000681521.1		c.1805C>T	p.Pro602Leu	missense	Exon 10 of 11	ENSP00000506037.1

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000557 AC: 138 AN: 247768 AF XY: 0.000461

Gnomad AFR exome AF: 0.000260

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00677

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000831

GnomAD4 exome AF: 0.000229 AC: 334 AN: 1461180 Hom.: 7 Cov.: 33 AF XY: 0.000172 AC XY: 125 AN XY: 726840

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00454 AC: 180 AN: 39682

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

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

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111590

Other (OTH) AF: 0.00235 AC: 142 AN: 60362

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74488

African (AFR) AF: 0.000217 AC: 9 AN: 41568

American (AMR) AF: 0.000261 AC: 4 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00771 AC: 40 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000273 Hom.: 2

Bravo AF: 0.000453

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000472 AC: 57

Asia WGS AF: 0.0120 AC: 42 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ASXL3-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.72
MVP		0.18
MPC		0.53
ClinPred		0.058	T
GERP RS		5.0
Varity_R		0.34
gMVP		0.39
Mutation Taster		=81/19	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: rs189786599; hg19: chr18-31319293;