rs726145

Variant names:

• chr18-33607946-C-A
• rs726145
• NM_030632.3:c.137+270C>A

Your query was ambiguous. Multiple possible variants found:

• chr18-33607946-C-A
• chr18-33607946-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_030632.3(ASXL3):​c.137+270C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 151,736 control chromosomes in the GnomAD database, including 8,118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.30 (8118 hom., cov: 32)
• Consequence: ASXL3 NM_030632.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.989
• Publications: 1 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: Illumina, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 18-33607946-C-A is Benign according to our data. Variant chr18-33607946-C-A is described in ClinVar as Benign. ClinVar VariationId is 1227429.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

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.137+270C>A		intron	N/A	NP_085135.1	Q9C0F0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL3	ENST00000269197.12	TSL:5 MANE Select	c.137+270C>A		intron	N/A	ENSP00000269197.4	Q9C0F0-1
	ASXL3	ENST00000696964.1		c.137+270C>A		intron	N/A	ENSP00000513003.1	A0A8V8TKV8
	ASXL3	ENST00000681521.1		c.137+270C>A		intron	N/A	ENSP00000506037.1	A0A7P0TAE5

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45009 AN: 151616 Hom.: 8124 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.505

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.0612

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.343

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.296 AC: 44989 AN: 151736 Hom.: 8118 Cov.: 32 AF XY: 0.292 AC XY: 21636 AN XY: 74130

African (AFR) AF: 0.113 AC: 4682 AN: 41464

American (AMR) AF: 0.295 AC: 4478 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 1501 AN: 3458

East Asian (EAS) AF: 0.0607 AC: 313 AN: 5154

South Asian (SAS) AF: 0.300 AC: 1446 AN: 4814

European-Finnish (FIN) AF: 0.307 AC: 3234 AN: 10544

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.413 AC: 28031 AN: 67796

Other (OTH) AF: 0.341 AC: 719 AN: 2106

Alfa AF: 0.349 Hom.: 12981

Bravo AF: 0.284

Asia WGS AF: 0.168 AC: 586 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.5
DANN	Benign	0.37
PhyloP100		0.99
Mutation Taster		=100/0	polymorphism (auto)

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: rs726145; hg19: chr18-31187910;