18-33578458-CCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCG-CCCGCCGCCGCCGCCGCCGCCGCCG

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_030632.3(ASXL3):​c.-141_-133delGCCGCCGCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 94,122 control chromosomes in the GnomAD database, including 17 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (12 hom., cov: 0)
  • Exomes 𝑓: 0.0062 (5 hom.)
• Consequence: ASXL3 NM_030632.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 18-33578458-CCCGCCGCCG-C is Benign according to our data. Variant chr18-33578458-CCCGCCGCCG-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1214936.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0111 (828/74552) while in subpopulation AFR AF = 0.028 (464/16552). AF 95% confidence interval is 0.0259. There are 12 homozygotes in GnomAd4. There are 377 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 828 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_-133delGCCGCCGCC		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_-133delGCCGCCGCC		5_prime_UTR	Exon 1 of 12	ENSP00000269197.4	Q9C0F0-1
	ASXL3	ENST00000696964.1		c.-141_-133delGCCGCCGCC		5_prime_UTR	Exon 1 of 13	ENSP00000513003.1	A0A8V8TKV8
	ASXL3	ENST00000681521.1		c.-141_-133delGCCGCCGCC		5_prime_UTR	Exon 1 of 11	ENSP00000506037.1	A0A7P0TAE5

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 832 AN: 74574 Hom.: 13 Cov.: 0

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00513

Gnomad ASJ AF: 0.00225

Gnomad EAS AF: 0.0247

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.00446

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00608

Gnomad OTH AF: 0.00655

GnomAD4 exome AF: 0.00618 AC: 121 AN: 19570 Hom.: 5 AF XY: 0.00691 AC XY: 89 AN XY: 12884

African (AFR) AF: 0.0345 AC: 4 AN: 116

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

Ashkenazi Jewish (ASJ) AF: 0.0169 AC: 2 AN: 118

East Asian (EAS) AF: 0.0440 AC: 24 AN: 546

South Asian (SAS) AF: 0.00371 AC: 4 AN: 1078

European-Finnish (FIN) AF: 0.00313 AC: 16 AN: 5112

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

European-Non Finnish (NFE) AF: 0.00559 AC: 66 AN: 11814

Other (OTH) AF: 0.00923 AC: 5 AN: 542

GnomAD4 genome AF: 0.0111 AC: 828 AN: 74552 Hom.: 12 Cov.: 0 AF XY: 0.0106 AC XY: 377 AN XY: 35410

African (AFR) AF: 0.0280 AC: 464 AN: 16552

American (AMR) AF: 0.00513 AC: 43 AN: 8380

Ashkenazi Jewish (ASJ) AF: 0.00225 AC: 5 AN: 2220

East Asian (EAS) AF: 0.0244 AC: 58 AN: 2380

South Asian (SAS) AF: 0.00273 AC: 5 AN: 1832

European-Finnish (FIN) AF: 0.00446 AC: 11 AN: 2466

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

European-Non Finnish (NFE) AF: 0.00601 AC: 236 AN: 39300

Other (OTH) AF: 0.00652 AC: 6 AN: 920

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		0.22

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;