18-33578458-CCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCG-CCCGCCGCCGCCGCCGCCG

Variant names:

• chr18-33578458-CCCGCCGCCGCCGCCG-C
• rs552419485
• NM_030632.3:c.-147_-133delGCCGCCGCCGCCGCC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_030632.3(ASXL3):​c.-147_-133delGCCGCCGCCGCCGCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 19,662 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0056 (7 hom., cov: 0)
  • Exomes 𝑓: 0.00051 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ASXL3 NM_030632.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.218
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000509 (10/19662) while in subpopulation AFR AF = 0.0254 (3/118). AF 95% confidence interval is 0.00693. There are 0 homozygotes in GnomAdExome4. There are 7 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 10 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL3	NM_030632.3	MANE Select	c.-147_-133delGCCGCCGCCGCCGCC		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.-147_-133delGCCGCCGCCGCCGCC		5_prime_UTR	Exon 1 of 12	ENSP00000269197.4	Q9C0F0-1
	ASXL3	ENST00000696964.1		c.-147_-133delGCCGCCGCCGCCGCC		5_prime_UTR	Exon 1 of 13	ENSP00000513003.1	A0A8V8TKV8
	ASXL3	ENST00000681521.1		c.-147_-133delGCCGCCGCCGCCGCC		5_prime_UTR	Exon 1 of 11	ENSP00000506037.1	A0A7P0TAE5

Frequencies

GnomAD3 genomes AF: 0.00558 AC: 416 AN: 74580 Hom.: 7 Cov.: 0

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00191

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00293

Gnomad SAS AF: 0.000539

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.0290

Gnomad NFE AF: 0.000356

Gnomad OTH AF: 0.00437

GnomAD4 exome AF: 0.000509 AC: 10 AN: 19662 Hom.: 0 AF XY: 0.000541 AC XY: 7 AN XY: 12946

African (AFR) AF: 0.0254 AC: 3 AN: 118

American (AMR) AF: 0.00 AC: 0 AN: 180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 118

East Asian (EAS) AF: 0.00 AC: 0 AN: 550

South Asian (SAS) AF: 0.00 AC: 0 AN: 1080

European-Finnish (FIN) AF: 0.000977 AC: 5 AN: 5116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 64

European-Non Finnish (NFE) AF: 0.000168 AC: 2 AN: 11886

Other (OTH) AF: 0.00 AC: 0 AN: 550

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00558 AC: 416 AN: 74558 Hom.: 7 Cov.: 0 AF XY: 0.00585 AC XY: 207 AN XY: 35412

African (AFR) AF: 0.0222 AC: 367 AN: 16552

American (AMR) AF: 0.00191 AC: 16 AN: 8380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2220

East Asian (EAS) AF: 0.00294 AC: 7 AN: 2380

South Asian (SAS) AF: 0.000546 AC: 1 AN: 1832

European-Finnish (FIN) AF: 0.00122 AC: 3 AN: 2466

Middle Eastern (MID) AF: 0.0313 AC: 4 AN: 128

European-Non Finnish (NFE) AF: 0.000356 AC: 14 AN: 39306

Other (OTH) AF: 0.00435 AC: 4 AN: 920

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.22

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;