rs143578678

chr18-33744850-G-A

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.5002G>A(p.Val1668Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00039 in 1,614,024 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (3 hom.)
• Consequence: ASXL3 NM_030632.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.61

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=0.007395923).
• BP6: Variant 18-33744850-G-A is Benign according to our data. Variant chr18-33744850-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-33744850-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00202 (307/152326) while in subpopulation AFR AF= 0.00707 (294/41570). AF 95% confidence interval is 0.00641. There are 2 homozygotes in gnomad4. There are 140 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 304 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASXL3	NM_030632.3	c.5002G>A	p.Val1668Met	missense_variant	12/12	ENST00000269197.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL3	ENST00000269197.12	c.5002G>A	p.Val1668Met	missense_variant	12/12	5	NM_030632.3	P4
ASXL3	ENST00000696964.1	c.5005G>A	p.Val1669Met	missense_variant	13/13			A2
ASXL3	ENST00000681521.1	c.4882G>A	p.Val1628Met	missense_variant	11/11			A2

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 304 AN: 152208 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00702

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000574 AC: 143 AN: 249212 Hom.: 1 AF XY: 0.000436 AC XY: 59 AN XY: 135208

Gnomad AFR exome AF: 0.00756

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000668

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000221 AC: 323 AN: 1461698 Hom.: 3 Cov.: 34 AF XY: 0.000180 AC XY: 131 AN XY: 727130

Gnomad4 AFR exome AF: 0.00717

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000663

GnomAD4 genome AF: 0.00202 AC: 307 AN: 152326 Hom.: 2 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74486

Gnomad4 AFR AF: 0.00707

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000348 Hom.: 0

Bravo AF: 0.00226

ESP6500AA AF: 0.00647 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000670 AC: 81

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2019	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ASXL3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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	0.13
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.96	N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.013
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.10	B
Vest4		0.15
MVP		0.068
MPC		0.13
ClinPred		0.034	T
GERP RS		2.0
Varity_R		0.070
gMVP		0.29

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: rs143578678; hg19: chr18-31324814;