18-33578458-CCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCG-CCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCG

Variant names:

• chr18-33578458-C-CCCGCCGCCG
• rs552419485
• NM_030632.3:c.-141_-133dupGCCGCCGCC

Variant summary

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

The NM_030632.3(ASXL3):​c.-141_-133dupGCCGCCGCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.013 (23 hom., cov: 0)
  • Exomes 𝑓: 0.00046 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ASXL3 NM_030632.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.593
• 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. GnomAd4 allele frequency = 0.0134 (996/74542) while in subpopulation AFR AF = 0.0395 (653/16544). AF 95% confidence interval is 0.037. There are 23 homozygotes in GnomAd4. There are 475 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 996 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.-141_-133dupGCCGCCGCC		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.-141_-133dupGCCGCCGCC		5_prime_UTR	Exon 1 of 12	ENSP00000269197.4	Q9C0F0-1
	ASXL3	ENST00000696964.1		c.-141_-133dupGCCGCCGCC		5_prime_UTR	Exon 1 of 13	ENSP00000513003.1	A0A8V8TKV8
	ASXL3	ENST00000681521.1		c.-141_-133dupGCCGCCGCC		5_prime_UTR	Exon 1 of 11	ENSP00000506037.1	A0A7P0TAE5

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 994 AN: 74564 Hom.: 23 Cov.: 0

Gnomad AFR AF: 0.0395

Gnomad AMI AF: 0.0134

Gnomad AMR AF: 0.00525

Gnomad ASJ AF: 0.00631

Gnomad EAS AF: 0.00460

Gnomad SAS AF: 0.00593

Gnomad FIN AF: 0.00324

Gnomad MID AF: 0.00725

Gnomad NFE AF: 0.00600

Gnomad OTH AF: 0.0131

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000458 AC: 9 AN: 19662 Hom.: 0 Cov.: 0 AF XY: 0.000618 AC XY: 8 AN XY: 12946

African (AFR) AF: 0.00847 AC: 1 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: 0.00278 AC: 3 AN: 1080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5116

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

European-Non Finnish (NFE) AF: 0.000421 AC: 5 AN: 11886

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

GnomAD4 genome AF: 0.0134 AC: 996 AN: 74542 Hom.: 23 Cov.: 0 AF XY: 0.0134 AC XY: 475 AN XY: 35406

African (AFR) AF: 0.0395 AC: 653 AN: 16544

American (AMR) AF: 0.00525 AC: 44 AN: 8380

Ashkenazi Jewish (ASJ) AF: 0.00631 AC: 14 AN: 2220

East Asian (EAS) AF: 0.00504 AC: 12 AN: 2380

South Asian (SAS) AF: 0.00600 AC: 11 AN: 1832

European-Finnish (FIN) AF: 0.00324 AC: 8 AN: 2466

Middle Eastern (MID) AF: 0.00781 AC: 1 AN: 128

European-Non Finnish (NFE) AF: 0.00601 AC: 236 AN: 39298

Other (OTH) AF: 0.0130 AC: 12 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		-0.59

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;