Variant 19-1753734-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001080488.2(ONECUT3):c.72C>G(p.Ser24Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000421 in 1,030,026 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

ONECUT3
NM_001080488.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.21

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06211388).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ONECUT3	NM_001080488.2 linkuse as main transcript	c.72C>G	p.Ser24Arg	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.72C>G	p.Ser24Arg	missense_variant	1/2	5	NM_001080488.2	ENSP00000371786.4		O60422

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

180

AN:

146940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00358

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000810

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000318

Gnomad OTH

AF:

0.000490

GnomAD4 exome

AF:

0.000288

AC:

254

AN:

882978

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

111

AN XY:

411884

show subpopulations

Gnomad4 AFR exome

AF:

0.00347

Gnomad4 AMR exome

AF:

0.000806

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000226

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.00122

AC:

180

AN:

147048

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

71582

show subpopulations

Gnomad4 AFR

AF:

0.00357

Gnomad4 AMR

AF:

0.000809

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000318

Gnomad4 OTH

AF:

0.000485

Alfa

AF:

0.00135

Hom.:

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

Aug 16, 2022

The c.72C>G (p.S24R) 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 72, causing the serine (S) at amino acid position 24 to be replaced by an arginine (R). 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

Pathogenic

0.76

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.036

Eigen

Benign

-0.058

Eigen_PC

Benign

-0.063

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.64

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.062

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-1.9

REVEL

Benign

0.055

Sift

Uncertain

0.0010

Sift4G

Benign

0.16

Polyphen

0.94

Vest4

0.072

MutPred

0.26

Gain of solvent accessibility (P = 0.0171);

MVP

0.46

ClinPred

0.22

GERP RS

1.4

Varity_R

0.34

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