20-32436404-C-T

Position:

• chr20-32436404-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015338.6(ASXL1):​c.3692C>T​(p.Ser1231Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00588 in 1,613,826 control chromosomes in the GnomAD database, including 489 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (61 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (428 hom.)
• Consequence: ASXL1 NM_015338.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 2.23

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001635164).
• BP6: Variant 20-32436404-C-T is Benign according to our data. Variant chr20-32436404-C-T is described in ClinVar as [Benign]. Clinvar id is 133586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32436404-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASXL1	NM_015338.6	c.3692C>T	p.Ser1231Phe	missense_variant	13/13	ENST00000375687.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL1	ENST00000375687.10	c.3692C>T	p.Ser1231Phe	missense_variant	13/13	5	NM_015338.6	P1

Frequencies

GnomAD3 genomes AF: 0.00920 AC: 1401 AN: 152204 Hom.: 62 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0728

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0200

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0203 AC: 5078 AN: 250264 Hom.: 316 AF XY: 0.0162 AC XY: 2188 AN XY: 135432

Gnomad AFR exome AF: 0.000988

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.0199

Gnomad SAS exome AF: 0.0114

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.00553 AC: 8089 AN: 1461504 Hom.: 428 Cov.: 31 AF XY: 0.00506 AC XY: 3678 AN XY: 727060

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.00295

Gnomad4 EAS exome AF: 0.0345

Gnomad4 SAS exome AF: 0.00975

Gnomad4 FIN exome AF: 0.000189

Gnomad4 NFE exome AF: 0.000154

Gnomad4 OTH exome AF: 0.00515

GnomAD4 genome AF: 0.00921 AC: 1403 AN: 152322 Hom.: 61 Cov.: 32 AF XY: 0.0104 AC XY: 777 AN XY: 74486

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.0729

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.0201

Gnomad4 SAS AF: 0.0126

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00455 Hom.: 49

Bravo AF: 0.0151

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0154 AC: 1874

Asia WGS AF: 0.0270 AC: 95 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 06, 2015	- -

Bohring-Opitz syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T;T;T;.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.096
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.77	.;T;.;T;T
MetaRNN	Benign	0.0016	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;L;.;.
MutationTaster	Benign	0.55	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.5	D;.;.;.;D
REVEL	Benign	0.024
Sift	Benign	0.073	T;.;.;.;T
Sift4G	Benign	0.075	T;T;T;.;T
Polyphen		0.030	B;B;B;.;.
Vest4		0.090
MPC		0.063
ClinPred		0.0090	T
GERP RS		3.6
Varity_R		0.095
gMVP		0.19

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

Publications

LitVar

Other links and lift over

dbSNP: rs74638057; hg19: chr20-31024207; COSMIC: COSV105900478; COSMIC: COSV105900478;