18-33578458-CCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCG-CCCGCCGCCGCCGCCGCCGCCGCCGCCG

Variant names:

• chr18-33578458-CCCGCCG-C
• rs552419485
• NM_030632.3:c.-138_-133delGCCGCC

Variant summary

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

The NM_030632.3(ASXL3):​c.-138_-133delGCCGCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 92,748 control chromosomes in the GnomAD database, including 17 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.011 (10 hom., cov: 0)
  • Exomes 𝑓: 0.057 (7 hom.)
• 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. GnomAd4 allele frequency = 0.0111 (824/74552) while in subpopulation AFR AF = 0.0207 (343/16558). AF 95% confidence interval is 0.0189. There are 10 homozygotes in GnomAd4. There are 375 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 824 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.-138_-133delGCCGCC		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.-138_-133delGCCGCC		5_prime_UTR	Exon 1 of 12	ENSP00000269197.4	Q9C0F0-1
	ASXL3	ENST00000696964.1		c.-138_-133delGCCGCC		5_prime_UTR	Exon 1 of 13	ENSP00000513003.1	A0A8V8TKV8
	ASXL3	ENST00000681521.1		c.-138_-133delGCCGCC		5_prime_UTR	Exon 1 of 11	ENSP00000506037.1	A0A7P0TAE5

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 824 AN: 74574 Hom.: 10 Cov.: 0

Gnomad AFR AF: 0.0207

Gnomad AMI AF: 0.0188

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.0108

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.00863

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.0290

Gnomad NFE AF: 0.00776

Gnomad OTH AF: 0.0164

GnomAD4 exome AF: 0.0573 AC: 1042 AN: 18196 Hom.: 7 AF XY: 0.0625 AC XY: 743 AN XY: 11888

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.115 AC: 12 AN: 104

American (AMR) AF: 0.0247 AC: 4 AN: 162

Ashkenazi Jewish (ASJ) AF: 0.0614 AC: 7 AN: 114

East Asian (EAS) AF: 0.117 AC: 53 AN: 454

South Asian (SAS) AF: 0.0458 AC: 45 AN: 982

European-Finnish (FIN) AF: 0.0204 AC: 100 AN: 4904

Middle Eastern (MID) AF: 0.0806 AC: 5 AN: 62

European-Non Finnish (NFE) AF: 0.0711 AC: 775 AN: 10904

Other (OTH) AF: 0.0804 AC: 41 AN: 510

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0111 AC: 824 AN: 74552 Hom.: 10 Cov.: 0 AF XY: 0.0106 AC XY: 375 AN XY: 35408

African (AFR) AF: 0.0207 AC: 343 AN: 16558

American (AMR) AF: 0.0121 AC: 101 AN: 8378

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 24 AN: 2220

East Asian (EAS) AF: 0.00252 AC: 6 AN: 2380

South Asian (SAS) AF: 0.00873 AC: 16 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: 0.00776 AC: 305 AN: 39302

Other (OTH) AF: 0.0164 AC: 15 AN: 916

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;