rs80040227

Positions:

• chr18-33738813-A-C
• chr18-33738813-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030632.3(ASXL3):​c.1409A>C​(p.His470Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,613,686 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (20 hom.)
• Consequence: ASXL3 NM_030632.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.789

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 (MetaRNN=0.004490763).
• BP6: Variant 18-33738813-A-C is Benign according to our data. Variant chr18-33738813-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 445897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00966 (1471/152330) while in subpopulation AFR AF= 0.0334 (1387/41574). AF 95% confidence interval is 0.0319. There are 18 homozygotes in gnomad4. There are 709 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1471 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASXL3	NM_030632.3	c.1409A>C	p.His470Pro	missense_variant	11/12	ENST00000269197.12	NP_085135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASXL3	ENST00000269197.12	c.1409A>C	p.His470Pro	missense_variant	11/12	5	NM_030632.3	ENSP00000269197	P4

Frequencies

GnomAD3 genomes AF: 0.00968 AC: 1473 AN: 152212 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0335

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

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: 0.0000882

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00257 AC: 638 AN: 248408 Hom.: 11 AF XY: 0.00178 AC XY: 240 AN XY: 134840

Gnomad AFR exome AF: 0.0363

Gnomad AMR exome AF: 0.00183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000711

Gnomad OTH exome AF: 0.000993

GnomAD4 exome AF: 0.00101 AC: 1469 AN: 1461356 Hom.: 20 Cov.: 33 AF XY: 0.000860 AC XY: 625 AN XY: 726974

Gnomad4 AFR exome AF: 0.0355

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000657

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00966 AC: 1471 AN: 152330 Hom.: 18 Cov.: 32 AF XY: 0.00952 AC XY: 709 AN XY: 74492

Gnomad4 AFR AF: 0.0334

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00126 Hom.: 8

Bravo AF: 0.0107

ESP6500AA AF: 0.0330 AC: 123

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00329 AC: 397

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 27, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.88
DEOGEN2	Benign	0.039	T;.
Eigen	Benign	-0.017
Eigen_PC	Benign	-0.016
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.54	T;T
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.063
Sift	Uncertain	0.023	D;.
Sift4G	Benign	0.20	T;.
Polyphen		0.91	P;.
Vest4		0.48
MVP		0.082
MPC		0.44
ClinPred		0.020	T
GERP RS		1.0
Varity_R		0.19
gMVP		0.59

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: rs80040227; hg19: chr18-31318777;