Variant 19-1754194-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001080488.2(ONECUT3):c.532C>G(p.Leu178Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00901 in 1,160,940 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0065 ( 4 hom., cov: 31)

Exomes 𝑓: 0.0094 ( 55 hom. )

Consequence

ONECUT3
NM_001080488.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.404

Variant links:

Genes affected

ONECUT3 (HGNC:13399): (one cut homeobox 3) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ONECUT3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0069778264).

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ONECUT3	NM_001080488.2 linkuse as main transcript	c.532C>G	p.Leu178Val	missense_variant	1/2	ENST00000382349.5	NP_001073957.1	O60422

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ONECUT3	ENST00000382349.5 linkuse as main transcript	c.532C>G	p.Leu178Val	missense_variant	1/2	5	NM_001080488.2	ENSP00000371786.4		O60422

Frequencies

GnomAD3 genomes

AF:

0.00654

AC:

959

AN:

146670

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.00659

Gnomad AMR

AF:

0.00244

Gnomad ASJ

AF:

0.00236

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.00838

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0114

Gnomad OTH

AF:

0.00692

GnomAD3 exomes

AF:

0.00479

AC:

192

AN:

40076

Hom.:

AF XY:

0.00474

AC XY:

115

AN XY:

24238

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.00170

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000608

Gnomad FIN exome

AF:

0.00861

Gnomad NFE exome

AF:

0.00942

Gnomad OTH exome

AF:

0.00168

GnomAD4 exome

AF:

0.00937

AC:

9503

AN:

1014164

Hom.:

Cov.:

AF XY:

0.00924

AC XY:

4572

AN XY:

494972

show subpopulations

Gnomad4 AFR exome

AF:

0.000794

Gnomad4 AMR exome

AF:

0.00166

Gnomad4 ASJ exome

AF:

0.00178

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00154

Gnomad4 FIN exome

AF:

0.00869

Gnomad4 NFE exome

AF:

0.0104

Gnomad4 OTH exome

AF:

0.00756

GnomAD4 genome

AF:

0.00654

AC:

960

AN:

146776

Hom.:

Cov.:

AF XY:

0.00636

AC XY:

455

AN XY:

71486

show subpopulations

Gnomad4 AFR

AF:

0.00146

Gnomad4 AMR

AF:

0.00243

Gnomad4 ASJ

AF:

0.00236

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00208

Gnomad4 FIN

AF:

0.00838

Gnomad4 NFE

AF:

0.0114

Gnomad4 OTH

AF:

0.00684

Alfa

AF:

0.0116

Hom.:

Bravo

AF:

0.00534

ExAC

AF:

0.00105

AC:

Asia WGS

AF:

0.00118

AC:

AN:

2564

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2023

The c.532C>G (p.L178V) alteration is located in exon 1 (coding exon 1) of the ONECUT3 gene. This alteration results from a C to G substitution at nucleotide position 532, causing the leucine (L) at amino acid position 178 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.055

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.38

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.0070

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.2

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.1

REVEL

Benign

0.15

Sift

Benign

0.056

Sift4G

Benign

0.18

Polyphen

0.99

Vest4

0.072

MVP

0.44

ClinPred

0.039

GERP RS

2.4

Varity_R

0.075

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over