Genetic Variant ASXL3:c.-144_-133delGCCGCCGCCGCC (chr18-33578458-CCCGCCGCCGCCG-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_030632.3(ASXL3):c.-144_-133delGCCGCCGCCGCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00559 in 94,208 control chromosomes in the GnomAD database, including 9 homozygotes. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0065 ( 9 hom., cov: 0)

Exomes 𝑓: 0.0023 ( 0 hom. )

Consequence

ASXL3
NM_030632.3 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.218

Publications

1 publications found

Variant links:

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

ASXL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00646 (482/74562) while in subpopulation AFR AF = 0.016 (265/16558). AF 95% confidence interval is 0.0144. There are 9 homozygotes in GnomAd4. There are 222 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 482 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.-144_-133delGCCGCCGCCGCC		5_prime_UTR	Exon 1 of 12	NP_085135.1	Q9C0F0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ASXL3	ENST00000269197.12	TSL:5 MANE Select	c.-144_-133delGCCGCCGCCGCC	5_prime_UTR	Exon 1 of 12	ENSP00000269197.4	Q9C0F0-1
ASXL3	ENST00000696964.1		c.-144_-133delGCCGCCGCCGCC	5_prime_UTR	Exon 1 of 13	ENSP00000513003.1	A0A8V8TKV8
ASXL3	ENST00000681521.1		c.-144_-133delGCCGCCGCCGCC	5_prime_UTR	Exon 1 of 11	ENSP00000506037.1	A0A7P0TAE5

Frequencies

GnomAD3 genomes

AF:

0.00646

AC:

482

AN:

74584

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0160

Gnomad AMI

AF:

0.0160

Gnomad AMR

AF:

0.00466

Gnomad ASJ

AF:

0.000901

Gnomad EAS

AF:

0.00962

Gnomad SAS

AF:

0.00863

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00725

Gnomad NFE

AF:

0.00318

Gnomad OTH

AF:

0.00546

GnomAD4 exome

AF:

0.00229

AC:

AN:

19646

Hom.:

AF XY:

0.00216

AC XY:

AN XY:

12934

show subpopulations

African (AFR)

AF:

0.00862

AC:

AN:

116

American (AMR)

AF:

0.00562

AC:

AN:

178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

118

East Asian (EAS)

AF:

0.00547

AC:

AN:

548

South Asian (SAS)

AF:

0.00556

AC:

AN:

1080

European-Finnish (FIN)

AF:

0.000195

AC:

AN:

5116

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00269

AC:

AN:

11878

Other (OTH)

AF:

0.00182

AC:

AN:

548

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00646

AC:

482

AN:

74562

Hom.:

Cov.:

AF XY:

0.00627

AC XY:

222

AN XY:

35410

show subpopulations

African (AFR)

AF:

0.0160

AC:

265

AN:

16558

American (AMR)

AF:

0.00466

AC:

AN:

8378

Ashkenazi Jewish (ASJ)

AF:

0.000901

AC:

AN:

2220

East Asian (EAS)

AF:

0.00966

AC:

AN:

2380

South Asian (SAS)

AF:

0.00873

AC:

AN:

1832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2466

Middle Eastern (MID)

AF:

0.00781

AC:

AN:

128

European-Non Finnish (NFE)

AF:

0.00318

AC:

125

AN:

39306

Other (OTH)

AF:

0.00543

AC:

AN:

920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

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

Publications

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18-33578458-CCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCG-CCCGCCGCCGCCGCCGCCGCCG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over