rs1234997614

Variant names:

• chr18-33578460-CGCCGCCGCCGCCG-C
• rs1234997614
• NM_030632.3:c.-171_-159delGCCGCCGCCGCCG

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.-171_-159delGCCGCCGCCGCCG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.013 (3 hom., cov: 0)
• Consequence: ASXL3 NM_030632.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.878
• Publications: 0 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 18-33578460-CGCCGCCGCCGCCG-C is Benign according to our data. Variant chr18-33578460-CGCCGCCGCCGCCG-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1199636.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (301/22630) while in subpopulation AFR AF = 0.0356 (273/7672). AF 95% confidence interval is 0.0321. There are 3 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 301 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.-171_-159delGCCGCCGCCGCCG		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.-171_-159delGCCGCCGCCGCCG		5_prime_UTR	Exon 1 of 12	ENSP00000269197.4	Q9C0F0-1
	ASXL3	ENST00000696964.1		c.-171_-159delGCCGCCGCCGCCG		5_prime_UTR	Exon 1 of 13	ENSP00000513003.1	A0A8V8TKV8
	ASXL3	ENST00000681521.1		c.-171_-159delGCCGCCGCCGCCG		5_prime_UTR	Exon 1 of 11	ENSP00000506037.1	A0A7P0TAE5

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 300 AN: 22628 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.0355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0114

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0133 AC: 301 AN: 22630 Hom.: 3 Cov.: 0 AF XY: 0.0119 AC XY: 132 AN XY: 11090

African (AFR) AF: 0.0356 AC: 273 AN: 7672

American (AMR) AF: 0.0143 AC: 24 AN: 1676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 450

East Asian (EAS) AF: 0.00 AC: 0 AN: 194

South Asian (SAS) AF: 0.00 AC: 0 AN: 436

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 30

European-Non Finnish (NFE) AF: 0.000103 AC: 1 AN: 9696

Other (OTH) AF: 0.0113 AC: 3 AN: 266

Alfa AF: 0.00152 Hom.: 0

ClinVar

ClinVar submissions as Germline

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		0.88

Splicing

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

Other links and lift over

dbSNP: rs1234997614; hg19: chr18-31158424;