chr18-33742984-G-T

Variant names:

• chr18-33742984-G-T
• rs376997378
• NM_030632.3:c.3136G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_030632.3(ASXL3):​c.3136G>T​(p.Gly1046Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,566 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1046R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ASXL3 NM_030632.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.31
• 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: Labcorp Genetics (formerly Invitae), Illumina, Orphanet, G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

LOC124904347 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-33742984-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 402202.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL3	NM_030632.3	MANE Select	c.3136G>T	p.Gly1046Trp	missense	Exon 12 of 12	NP_085135.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL3	ENST00000269197.12	TSL:5 MANE Select	c.3136G>T	p.Gly1046Trp	missense	Exon 12 of 12	ENSP00000269197.4
	ASXL3	ENST00000696964.1		c.3139G>T	p.Gly1047Trp	missense	Exon 13 of 13	ENSP00000513003.1
	ASXL3	ENST00000681521.1		c.3016G>T	p.Gly1006Trp	missense	Exon 11 of 11	ENSP00000506037.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461566 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727062

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111786

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.97	L
PhyloP100		9.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.25	T
Polyphen		1.0	D
Vest4		0.76
MutPred		0.23		Loss of methylation at R1047 (P = 0.0185)
MVP		0.12
MPC		0.57
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.34
gMVP		0.58
Mutation Taster		=47/53	disease causing

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

Other links and lift over

dbSNP: rs376997378; hg19: chr18-31322948;