NM_030632.3:c.54+222_54+231dupTCCGGGACCG

Variant names:

• chr18-33578904-G-GCGTCCGGGAC
• rs570670779
• NM_030632.3:c.54+222_54+231dupTCCGGGACCG

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.54+222_54+231dupTCCGGGACCG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00482 in 205,018 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0063 (8 hom., cov: 31)
  • Exomes 𝑓: 0.00055 (0 hom.)
• Consequence: ASXL3 NM_030632.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.672
• 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 18-33578904-G-GCGTCCGGGAC is Benign according to our data. Variant chr18-33578904-G-GCGTCCGGGAC is described in ClinVar as Likely_benign. ClinVar VariationId is 1203778.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00631 (959/152034) while in subpopulation AFR AF = 0.022 (915/41548). AF 95% confidence interval is 0.0208. There are 8 homozygotes in GnomAd4. There are 477 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 959 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.54+222_54+231dupTCCGGGACCG		intron	N/A	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.54+222_54+231dupTCCGGGACCG		intron	N/A	ENSP00000269197.4	Q9C0F0-1
	ASXL3	ENST00000642541.1		c.-649_-640dupTCCGGGACCG		5_prime_UTR	Exon 1 of 15	ENSP00000493665.1	A0A2R8Y461
	ASXL3	ENST00000696964.1		c.54+222_54+231dupTCCGGGACCG		intron	N/A	ENSP00000513003.1	A0A8V8TKV8

Frequencies

GnomAD3 genomes AF: 0.00623 AC: 946 AN: 151918 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00480

GnomAD4 exome AF: 0.000547 AC: 29 AN: 52984 Hom.: 0 Cov.: 0 AF XY: 0.000485 AC XY: 14 AN XY: 28838

African (AFR) AF: 0.0179 AC: 19 AN: 1062

American (AMR) AF: 0.000693 AC: 1 AN: 1442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1290

East Asian (EAS) AF: 0.00 AC: 0 AN: 2102

South Asian (SAS) AF: 0.00 AC: 0 AN: 680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 242

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 37614

Other (OTH) AF: 0.00301 AC: 9 AN: 2988

GnomAD4 genome AF: 0.00631 AC: 959 AN: 152034 Hom.: 8 Cov.: 31 AF XY: 0.00642 AC XY: 477 AN XY: 74318

African (AFR) AF: 0.0220 AC: 915 AN: 41548

American (AMR) AF: 0.00203 AC: 31 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67908

Other (OTH) AF: 0.00475 AC: 10 AN: 2106

Alfa AF: 0.00556 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		0.67
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs570670779; hg19: chr18-31158868;