chr18-33740369-C-G

Variant names:

• chr18-33740369-C-G
• rs190659120
• NM_030632.3:c.2965C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030632.3(ASXL3):​c.2965C>G​(p.Arg989Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,609,562 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (9 hom.)
• Consequence: ASXL3 NM_030632.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.48
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010617167).
• BP6: Variant 18-33740369-C-G is Benign according to our data. Variant chr18-33740369-C-G is described in ClinVar as Benign. ClinVar VariationId is 389938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0012 (183/152194) while in subpopulation NFE AF = 0.0019 (129/68008). AF 95% confidence interval is 0.00163. There are 2 homozygotes in GnomAd4. There are 86 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 183 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL3	NM_030632.3	MANE Select	c.2965C>G	p.Arg989Gly	missense	Exon 11 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.2965C>G	p.Arg989Gly	missense	Exon 11 of 12	ENSP00000269197.4
	ASXL3	ENST00000696964.1		c.2968C>G	p.Arg990Gly	missense	Exon 12 of 13	ENSP00000513003.1
	ASXL3	ENST00000681521.1		c.2845C>G	p.Arg949Gly	missense	Exon 10 of 11	ENSP00000506037.1

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152076 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00191

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00119 AC: 288 AN: 241826 AF XY: 0.00119

Gnomad AFR exome AF: 0.000403

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.000824

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.00189

Gnomad OTH exome AF: 0.000515

GnomAD4 exome AF: 0.00188 AC: 2746 AN: 1457368 Hom.: 9 Cov.: 33 AF XY: 0.00189 AC XY: 1368 AN XY: 724682

African (AFR) AF: 0.000331 AC: 11 AN: 33206

American (AMR) AF: 0.00139 AC: 61 AN: 43852

Ashkenazi Jewish (ASJ) AF: 0.00170 AC: 44 AN: 25878

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.000573 AC: 49 AN: 85494

European-Finnish (FIN) AF: 0.000319 AC: 17 AN: 53274

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5746

European-Non Finnish (NFE) AF: 0.00221 AC: 2450 AN: 1110156

Other (OTH) AF: 0.00170 AC: 102 AN: 60130

GnomAD4 genome AF: 0.00120 AC: 183 AN: 152194 Hom.: 2 Cov.: 33 AF XY: 0.00116 AC XY: 86 AN XY: 74398

African (AFR) AF: 0.000265 AC: 11 AN: 41542

American (AMR) AF: 0.00183 AC: 28 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4808

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00190 AC: 129 AN: 68008

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00133 Hom.: 2

Bravo AF: 0.00119

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00219 AC: 18

ExAC AF: 0.00137 AC: 166

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	ASXL3-related disorder (1)
-	-	1	not specified (1)
-	-	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	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.5
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.95	P
Vest4		0.91
MVP		0.70
MPC		0.15
ClinPred		0.045	T
GERP RS		5.0
Varity_R		0.20
gMVP		0.39
Mutation Taster		=71/29	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: rs190659120; hg19: chr18-31320333;