rs6057581

chr20-32436685-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.3973C>T(p.Leu1325Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00522 in 1,613,986 control chromosomes in the GnomAD database, including 333 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 0.028 (186 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (147 hom.)
• Consequence: ASXL1 NM_015338.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -0.314

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=0.0017579794).
• BP6: Variant 20-32436685-C-T is Benign according to our data. Variant chr20-32436685-C-T is described in ClinVar as [Benign]. Clinvar id is 133589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-32436685-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASXL1	NM_015338.6	c.3973C>T	p.Leu1325Phe	missense_variant	13/13	ENST00000375687.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL1	ENST00000375687.10	c.3973C>T	p.Leu1325Phe	missense_variant	13/13	5	NM_015338.6	P1

Frequencies

GnomAD3 genomes AF: 0.0277 AC: 4210 AN: 152168 Hom.: 184 Cov.: 32

Gnomad AFR AF: 0.0959

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0181

GnomAD3 exomes AF: 0.00706 AC: 1773 AN: 251160 Hom.: 74 AF XY: 0.00523 AC XY: 711 AN XY: 135838

Gnomad AFR exome AF: 0.0948

Gnomad AMR exome AF: 0.00457

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000528

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00287 AC: 4194 AN: 1461700 Hom.: 147 Cov.: 42 AF XY: 0.00242 AC XY: 1763 AN XY: 727162

Gnomad4 AFR exome AF: 0.0932

Gnomad4 AMR exome AF: 0.00510

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000346

Gnomad4 OTH exome AF: 0.00684

GnomAD4 genome AF: 0.0278 AC: 4228 AN: 152286 Hom.: 186 Cov.: 32 AF XY: 0.0268 AC XY: 1994 AN XY: 74462

Gnomad4 AFR AF: 0.0960

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00485 Hom.: 48

Bravo AF: 0.0313

ESP6500AA AF: 0.0876 AC: 386

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00894 AC: 1085

Asia WGS AF: 0.00606 AC: 22 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2 Other:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2018	- -

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	0.11
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T;.;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.15	N
MetaRNN	Benign	0.0018	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;M;M;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N;.;.;.;N
REVEL	Benign	0.051
Sift	Uncertain	0.0070	D;.;.;.;D
Sift4G	Benign	0.70	T;T;T;.;T
Polyphen		0.99	D;D;D;.;.
Vest4		0.23
MVP		0.22
MPC		0.29
ClinPred		0.018	T
GERP RS		1.3
Varity_R		0.032
gMVP		0.099

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

Publications

LitVar

Other links and lift over

dbSNP: rs6057581; hg19: chr20-31024488; COSMIC: COSV60105175; COSMIC: COSV60105175;