chr18-33646335-C-T

Variant names:

• chr18-33646335-C-T
• rs1440478761
• NM_030632.3:c.337C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_030632.3(ASXL3):​c.337C>T​(p.His113Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,608,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H113R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ASXL3 NM_030632.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.37
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055556297).

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.337C>T	p.His113Tyr	missense	Exon 4 of 12	NP_085135.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL3	ENST00000269197.12	TSL:5 MANE Select	c.337C>T	p.His113Tyr	missense	Exon 4 of 12	ENSP00000269197.4
	ASXL3	ENST00000696964.1		c.340C>T	p.His114Tyr	missense	Exon 5 of 13	ENSP00000513003.1
	ASXL3	ENST00000681521.1		c.337C>T	p.His113Tyr	missense	Exon 4 of 11	ENSP00000506037.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151924 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000810 AC: 2 AN: 246858 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000560

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000894

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1456950 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 724780

African (AFR) AF: 0.00 AC: 0 AN: 33248

American (AMR) AF: 0.00 AC: 0 AN: 44344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25958

East Asian (EAS) AF: 0.00 AC: 0 AN: 39532

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1108888

Other (OTH) AF: 0.00 AC: 0 AN: 60130

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151924 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74202

African (AFR) AF: 0.00 AC: 0 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15216

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67970

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	16
DANN	Benign	0.53
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.4
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.053
Sift	Benign	0.073	T
Sift4G	Uncertain	0.033	D
Polyphen		0.054	B
Vest4		0.19
MutPred		0.18		Gain of helix (P = 0.027)
MVP		0.043
MPC		0.14
ClinPred		0.061	T
GERP RS		-2.1
Varity_R		0.051
gMVP		0.15
Mutation Taster		=95/5	polymorphism

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: rs1440478761; hg19: chr18-31226299;