rs199974440

Positions:

• chr18-33739861-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_030632.3(ASXL3):​c.2457T>C​(p.Ala819=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00474 in 1,613,876 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (37 hom.)
• Consequence: ASXL3 NM_030632.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.444

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 18-33739861-T-C is Benign according to our data. Variant chr18-33739861-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 210370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.444 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00315 (480/152244) while in subpopulation NFE AF= 0.00578 (393/68020). AF 95% confidence interval is 0.00531. There are 2 homozygotes in gnomad4. There are 208 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 480 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASXL3	NM_030632.3	c.2457T>C	p.Ala819=	synonymous_variant	11/12	ENST00000269197.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL3	ENST00000269197.12	c.2457T>C	p.Ala819=	synonymous_variant	11/12	5	NM_030632.3	P4

Frequencies

GnomAD3 genomes AF: 0.00317 AC: 482 AN: 152126 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00578

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00399 AC: 994 AN: 248940 Hom.: 5 AF XY: 0.00456 AC XY: 616 AN XY: 135048

Gnomad AFR exome AF: 0.000582

Gnomad AMR exome AF: 0.000667

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00579

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.00622

Gnomad OTH exome AF: 0.00513

GnomAD4 exome AF: 0.00491 AC: 7171 AN: 1461632 Hom.: 37 Cov.: 33 AF XY: 0.00511 AC XY: 3715 AN XY: 727092

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00567

Gnomad4 FIN exome AF: 0.00238

Gnomad4 NFE exome AF: 0.00558

Gnomad4 OTH exome AF: 0.00368

GnomAD4 genome AF: 0.00315 AC: 480 AN: 152244 Hom.: 2 Cov.: 32 AF XY: 0.00279 AC XY: 208 AN XY: 74448

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00578

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00496 Hom.: 7

Bravo AF: 0.00306

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00453

EpiControl AF: 0.00564

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ASXL3: BP4, BP7, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 15, 2017

- -

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
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.0
DANN	Benign	0.42

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: rs199974440; hg19: chr18-31319825;