18-33743312-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_030632.3(ASXL3):c.3464C>T(p.Ser1155Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,844 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1155S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 1 hom. )

Consequence

ASXL3
NM_030632.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.31

Publications

4 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: Labcorp Genetics (formerly Invitae), Illumina, Orphanet, G2P
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ASXL3 links:

LOC124904347 (HGNC:):

LOC124904347 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30631065).

BP6

Variant 18-33743312-C-T is Benign according to our data. Variant chr18-33743312-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434427.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000226 (33/1461548) while in subpopulation MID AF = 0.00052 (3/5768). AF 95% confidence interval is 0.00023. There are 1 homozygotes in GnomAdExome4. There are 17 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 33 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.3464C>T	p.Ser1155Leu	missense	Exon 12 of 12	NP_085135.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ASXL3	ENST00000269197.12	TSL:5 MANE Select	c.3464C>T	p.Ser1155Leu	missense	Exon 12 of 12	ENSP00000269197.4
ASXL3	ENST00000696964.1		c.3467C>T	p.Ser1156Leu	missense	Exon 13 of 13	ENSP00000513003.1
ASXL3	ENST00000681521.1		c.3344C>T	p.Ser1115Leu	missense	Exon 11 of 11	ENSP00000506037.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000282

AC:

AN:

248660

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000355

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461548

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727052

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111808

Other (OTH)

AF:

0.000133

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.0000131

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74462

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000481

AC:

AN:

41554

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000782

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000248

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not specified (1)

Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.049

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.011

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.0

PhyloP100

3.3

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.7

REVEL

Benign

0.25

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.27

MutPred

0.17

Loss of glycosylation at S1155 (P = 0.0226)

MVP

0.60

MPC

0.098

ClinPred

0.53

GERP RS

5.9

Varity_R

0.15

gMVP

0.28

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over