chr18-33578458-C-CCCG

Variant names:

• chr18-33578458-C-CCCG
• rs552419485
• NM_030632.3:c.-135_-133dupGCC

Variant summary

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

The NM_030632.3(ASXL3):​c.-135_-133dupGCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.068 (229 hom., cov: 0)
  • Exomes 𝑓: 0.034 (2 hom.)
• Consequence: ASXL3 NM_030632.3 5_prime_UTR
• Clinical Significance: 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: Illumina, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• 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-CCCG is Benign according to our data. Variant chr18-33578458-C-CCCG is described in ClinVar as Benign. ClinVar VariationId is 1296668.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0766 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.-135_-133dupGCC		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.-135_-133dupGCC		5_prime_UTR	Exon 1 of 12	ENSP00000269197.4	Q9C0F0-1
	ASXL3	ENST00000696964.1		c.-135_-133dupGCC		5_prime_UTR	Exon 1 of 13	ENSP00000513003.1	A0A8V8TKV8
	ASXL3	ENST00000681521.1		c.-135_-133dupGCC		5_prime_UTR	Exon 1 of 11	ENSP00000506037.1	A0A7P0TAE5

Frequencies

GnomAD3 genomes AF: 0.0683 AC: 5087 AN: 74488 Hom.: 229 Cov.: 0

Gnomad AFR AF: 0.0534

Gnomad AMI AF: 0.0188

Gnomad AMR AF: 0.0576

Gnomad ASJ AF: 0.0797

Gnomad EAS AF: 0.0272

Gnomad SAS AF: 0.0383

Gnomad FIN AF: 0.0987

Gnomad MID AF: 0.0435

Gnomad NFE AF: 0.0790

Gnomad OTH AF: 0.0579

GnomAD4 exome AF: 0.0339 AC: 662 AN: 19536 Hom.: 2 Cov.: 0 AF XY: 0.0307 AC XY: 395 AN XY: 12854

African (AFR) AF: 0.0169 AC: 2 AN: 118

American (AMR) AF: 0.00556 AC: 1 AN: 180

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 3 AN: 116

East Asian (EAS) AF: 0.00912 AC: 5 AN: 548

South Asian (SAS) AF: 0.0260 AC: 28 AN: 1078

European-Finnish (FIN) AF: 0.0676 AC: 343 AN: 5076

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

European-Non Finnish (NFE) AF: 0.0227 AC: 268 AN: 11808

Other (OTH) AF: 0.0219 AC: 12 AN: 548

GnomAD4 genome AF: 0.0683 AC: 5087 AN: 74466 Hom.: 229 Cov.: 0 AF XY: 0.0679 AC XY: 2400 AN XY: 35370

African (AFR) AF: 0.0536 AC: 886 AN: 16536

American (AMR) AF: 0.0575 AC: 481 AN: 8360

Ashkenazi Jewish (ASJ) AF: 0.0797 AC: 177 AN: 2220

East Asian (EAS) AF: 0.0273 AC: 65 AN: 2380

South Asian (SAS) AF: 0.0388 AC: 71 AN: 1830

European-Finnish (FIN) AF: 0.0987 AC: 243 AN: 2462

Middle Eastern (MID) AF: 0.0313 AC: 4 AN: 128

European-Non Finnish (NFE) AF: 0.0790 AC: 3100 AN: 39258

Other (OTH) AF: 0.0576 AC: 53 AN: 920

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: 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;