18-33578458-CCCGCCGCCG-C

Position:

• chr18-33578458-CCCGCCGCCG-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 828 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASXL3	NM_030632.3	c.-141_-133delGCCGCCGCC		5_prime_UTR_variant	1/12	ENST00000269197.12	NP_085135.1
ASXL3	XM_005258356.2	c.-141_-133delGCCGCCGCC		5_prime_UTR_variant	1/13		XP_005258413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASXL3	ENST00000269197	c.-141_-133delGCCGCCGCC		5_prime_UTR_variant	1/12	5	NM_030632.3	ENSP00000269197.4
ASXL3	ENST00000696964	c.-141_-133delGCCGCCGCC		5_prime_UTR_variant	1/13			ENSP00000513003.1
ASXL3	ENST00000681521	c.-141_-133delGCCGCCGCC		5_prime_UTR_variant	1/11			ENSP00000506037.1

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

Gnomad4 AFR exome AF: 0.0345

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0169

Gnomad4 EAS exome AF: 0.0440

Gnomad4 SAS exome AF: 0.00371

Gnomad4 FIN exome AF: 0.00313

Gnomad4 NFE exome AF: 0.00559

Gnomad4 OTH exome AF: 0.00923

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

Gnomad4 AFR AF: 0.0280

Gnomad4 AMR AF: 0.00513

Gnomad4 ASJ AF: 0.00225

Gnomad4 EAS AF: 0.0244

Gnomad4 SAS AF: 0.00273

Gnomad4 FIN AF: 0.00446

Gnomad4 NFE AF: 0.00601

Gnomad4 OTH AF: 0.00652

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs552419485; hg19: chr18-31158422;