18-33578458-CCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCG-CCCGCCGCCGCCGCCGCCGCCGCCGCCGCCG

Variant names:

• chr18-33578458-CCCG-C
• rs552419485
• NM_030632.3:c.-135_-133delGCC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_030632.3(ASXL3):​c.-135_-133delGCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 93,656 control chromosomes in the GnomAD database, including 13,990 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.55 (11626 hom., cov: 0)
  • Exomes 𝑓: 0.54 (2364 hom.)
• Consequence: ASXL3 NM_030632.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00300
• Publications: 1 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Illumina
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 18-33578458-CCCG-C is Benign according to our data. Variant chr18-33578458-CCCG-C is described in ClinVar as Benign. ClinVar VariationId is 1296078.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.704 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL3	NM_030632.3	MANE Select	c.-135_-133delGCC		5_prime_UTR	Exon 1 of 12	NP_085135.1	Q9C0F0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL3	ENST00000269197.12	TSL:5 MANE Select	c.-135_-133delGCC		5_prime_UTR	Exon 1 of 12	ENSP00000269197.4	Q9C0F0-1
	ASXL3	ENST00000696964.1		c.-135_-133delGCC		5_prime_UTR	Exon 1 of 13	ENSP00000513003.1	A0A8V8TKV8
	ASXL3	ENST00000681521.1		c.-135_-133delGCC		5_prime_UTR	Exon 1 of 11	ENSP00000506037.1	A0A7P0TAE5

Frequencies

GnomAD3 genomes AF: 0.547 AC: 40637 AN: 74300 Hom.: 11639 Cov.: 0

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.583

Gnomad AMR AF: 0.626

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.733

Gnomad SAS AF: 0.582

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.515

Gnomad NFE AF: 0.561

Gnomad OTH AF: 0.558

GnomAD4 exome AF: 0.542 AC: 10496 AN: 19378 Hom.: 2364 AF XY: 0.552 AC XY: 7051 AN XY: 12762

African (AFR) AF: 0.585 AC: 69 AN: 118

American (AMR) AF: 0.653 AC: 115 AN: 176

Ashkenazi Jewish (ASJ) AF: 0.576 AC: 68 AN: 118

East Asian (EAS) AF: 0.635 AC: 344 AN: 542

South Asian (SAS) AF: 0.590 AC: 629 AN: 1066

European-Finnish (FIN) AF: 0.479 AC: 2397 AN: 5000

Middle Eastern (MID) AF: 0.625 AC: 40 AN: 64

European-Non Finnish (NFE) AF: 0.555 AC: 6516 AN: 11744

Other (OTH) AF: 0.578 AC: 318 AN: 550

GnomAD4 genome AF: 0.547 AC: 40619 AN: 74278 Hom.: 11626 Cov.: 0 AF XY: 0.546 AC XY: 19257 AN XY: 35268

African (AFR) AF: 0.468 AC: 7720 AN: 16486

American (AMR) AF: 0.626 AC: 5227 AN: 8348

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 1342 AN: 2206

East Asian (EAS) AF: 0.733 AC: 1739 AN: 2372

South Asian (SAS) AF: 0.580 AC: 1061 AN: 1828

European-Finnish (FIN) AF: 0.315 AC: 775 AN: 2458

Middle Eastern (MID) AF: 0.524 AC: 66 AN: 126

European-Non Finnish (NFE) AF: 0.561 AC: 21960 AN: 39164

Other (OTH) AF: 0.558 AC: 512 AN: 918

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0030
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs552419485; hg19: chr18-31158422;