18-33578458-CCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCG-CCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCG

Variant names:

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

Variant summary

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

The NM_030632.3(ASXL3):​c.-138_-133dupGCCGCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.039 (105 hom., cov: 0)
  • Exomes 𝑓: 0.0030 (1 hom.)
• Consequence: ASXL3 NM_030632.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 18-33578458-C-CCCGCCG is Benign according to our data. Variant chr18-33578458-C-CCCGCCG is described in ClinVar as Likely_benign. ClinVar VariationId is 1203880.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0797 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.-138_-133dupGCCGCC		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_-133dupGCCGCC		5_prime_UTR	Exon 1 of 12	ENSP00000269197.4	Q9C0F0-1
	ASXL3	ENST00000696964.1		c.-138_-133dupGCCGCC		5_prime_UTR	Exon 1 of 13	ENSP00000513003.1	A0A8V8TKV8
	ASXL3	ENST00000681521.1		c.-138_-133dupGCCGCC		5_prime_UTR	Exon 1 of 11	ENSP00000506037.1	A0A7P0TAE5

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 2873 AN: 74548 Hom.: 107 Cov.: 0

Gnomad AFR AF: 0.0836

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0338

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.0126

Gnomad SAS AF: 0.0248

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.0145

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0492

GnomAD4 exome AF: 0.00301 AC: 59 AN: 19628 Hom.: 1 Cov.: 0 AF XY: 0.00255 AC XY: 33 AN XY: 12922

African (AFR) AF: 0.00847 AC: 1 AN: 118

American (AMR) AF: 0.00 AC: 0 AN: 178

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

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

South Asian (SAS) AF: 0.0130 AC: 14 AN: 1078

European-Finnish (FIN) AF: 0.00293 AC: 15 AN: 5112

Middle Eastern (MID) AF: 0.0156 AC: 1 AN: 64

European-Non Finnish (NFE) AF: 0.00228 AC: 27 AN: 11860

Other (OTH) AF: 0.00182 AC: 1 AN: 550

GnomAD4 genome AF: 0.0385 AC: 2870 AN: 74526 Hom.: 105 Cov.: 0 AF XY: 0.0366 AC XY: 1297 AN XY: 35396

African (AFR) AF: 0.0834 AC: 1379 AN: 16538

American (AMR) AF: 0.0338 AC: 283 AN: 8380

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 41 AN: 2220

East Asian (EAS) AF: 0.0126 AC: 30 AN: 2380

South Asian (SAS) AF: 0.0251 AC: 46 AN: 1832

European-Finnish (FIN) AF: 0.0130 AC: 32 AN: 2466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 128

European-Non Finnish (NFE) AF: 0.0256 AC: 1005 AN: 39290

Other (OTH) AF: 0.0490 AC: 45 AN: 918

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely 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		-0.59

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;