chr20-32436471-T-C

Variant names:

• chr20-32436471-T-C
• rs4911231
• NM_015338.6:c.3759T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015338.6(ASXL1):​c.3759T>C​(p.Ser1253Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 1,613,818 control chromosomes in the GnomAD database, including 127,377 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10527 hom., cov: 33)
  • Exomes 𝑓: 0.39 (116850 hom.)
• Consequence: ASXL1 NM_015338.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.429
• Publications: 37 publications found

Genes affected

ASXL1 (HGNC:18318): (ASXL transcriptional regulator 1) This gene is similar to the Drosophila additional sex combs gene, which encodes a chromatin-binding protein required for normal determination of segment identity in the developing embryo. The protein is a member of the Polycomb group of proteins, which are necessary for the maintenance of stable repression of homeotic and other loci. The protein is thought to disrupt chromatin in localized areas, enhancing transcription of certain genes while repressing the transcription of other genes. The protein encoded by this gene functions as a ligand-dependent co-activator for retinoic acid receptor in cooperation with nuclear receptor coactivator 1. Mutations in this gene are associated with myelodysplastic syndromes and chronic myelomonocytic leukemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

ASXL1 Gene-Disease associations (from GenCC):

• Bohring-Opitz syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Laboratory for Molecular Medicine, G2P, Illumina

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 20-32436471-T-C is Benign according to our data. Variant chr20-32436471-T-C is described in ClinVar as Benign. ClinVar VariationId is 338113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.429 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015338.6. 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
	ASXL1	NM_015338.6	MANE Select	c.3759T>C	p.Ser1253Ser	synonymous	Exon 13 of 13	NP_056153.2
	ASXL1	NM_001363734.1		c.3576T>C	p.Ser1192Ser	synonymous	Exon 12 of 12	NP_001350663.1	A0A2R8Y5U1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL1	ENST00000375687.10	TSL:5 MANE Select	c.3759T>C	p.Ser1253Ser	synonymous	Exon 13 of 13	ENSP00000364839.4	Q8IXJ9-1
	ASXL1	ENST00000306058.9	TSL:1	c.3744T>C	p.Ser1248Ser	synonymous	Exon 12 of 12	ENSP00000305119.5	Q76L82
	ASXL1	ENST00000905973.1		c.3756T>C	p.Ser1252Ser	synonymous	Exon 12 of 12	ENSP00000576032.1

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53576 AN: 151994 Hom.: 10515 Cov.: 33

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.737

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.347

GnomAD2 exomes AF: 0.424 AC: 106546 AN: 251140 AF XY: 0.422

Gnomad AFR exome AF: 0.196

Gnomad AMR exome AF: 0.481

Gnomad ASJ exome AF: 0.326

Gnomad EAS exome AF: 0.774

Gnomad FIN exome AF: 0.469

Gnomad NFE exome AF: 0.389

Gnomad OTH exome AF: 0.392

GnomAD4 exome AF: 0.393 AC: 574814 AN: 1461706 Hom.: 116850 Cov.: 67 AF XY: 0.392 AC XY: 285353 AN XY: 727168

African (AFR) AF: 0.193 AC: 6449 AN: 33478

American (AMR) AF: 0.471 AC: 21073 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 8594 AN: 26136

East Asian (EAS) AF: 0.722 AC: 28666 AN: 39700

South Asian (SAS) AF: 0.413 AC: 35630 AN: 86258

European-Finnish (FIN) AF: 0.472 AC: 25160 AN: 53302

Middle Eastern (MID) AF: 0.290 AC: 1670 AN: 5768

European-Non Finnish (NFE) AF: 0.381 AC: 424121 AN: 1111950

Other (OTH) AF: 0.388 AC: 23451 AN: 60392

GnomAD4 genome AF: 0.352 AC: 53608 AN: 152112 Hom.: 10527 Cov.: 33 AF XY: 0.360 AC XY: 26782 AN XY: 74378

African (AFR) AF: 0.198 AC: 8202 AN: 41512

American (AMR) AF: 0.396 AC: 6051 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 1111 AN: 3472

East Asian (EAS) AF: 0.738 AC: 3820 AN: 5176

South Asian (SAS) AF: 0.430 AC: 2075 AN: 4824

European-Finnish (FIN) AF: 0.467 AC: 4942 AN: 10578

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.385 AC: 26195 AN: 67958

Other (OTH) AF: 0.345 AC: 727 AN: 2108

Alfa AF: 0.363 Hom.: 8133

Bravo AF: 0.346

Asia WGS AF: 0.492 AC: 1710 AN: 3478

EpiCase AF: 0.362

EpiControl AF: 0.367

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Bohring-Opitz syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.2
DANN	Benign	0.67
PhyloP100		0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4911231; hg19: chr20-31024274; COSMIC: COSV60102318; COSMIC: COSV60102318;