dbSNP rs1302854088: ONECUT3:p.Pro25Gln (chr19-1753736-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001080488.2(ONECUT3):c.74C>A(p.Pro25Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P25R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ONECUT3
NM_001080488.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.14

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20982677).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ONECUT3	NM_001080488.2 link	c.74C>A	p.Pro25Gln	missense_variant	Exon 1 of 2	ENST00000382349.5	NP_001073957.1	O60422

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ONECUT3	ENST00000382349.5 link	c.74C>A	p.Pro25Gln	missense_variant	Exon 1 of 2	5	NM_001080488.2	ENSP00000371786.4		O60422

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

878738

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

409694

African (AFR)

AF:

0.00

AC:

AN:

16628

American (AMR)

AF:

0.00

AC:

AN:

2364

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6404

East Asian (EAS)

AF:

0.00

AC:

AN:

6422

South Asian (SAS)

AF:

0.00

AC:

AN:

17686

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1832

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

792230

Other (OTH)

AF:

0.00

AC:

AN:

29900

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.74C>A (p.P25Q) alteration is located in exon 1 (coding exon 1) of the ONECUT3 gene. This alteration results from a C to A substitution at nucleotide position 74, causing the proline (P) at amino acid position 25 to be replaced by a glutamine (Q). 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

0.18

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.020

Eigen

Benign

0.044

Eigen_PC

Benign

0.048

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.63

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.21

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

2.1

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-2.3

REVEL

Benign

0.085

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.010

Polyphen

0.97

Vest4

0.10

MutPred

0.20

Gain of helix (P = 0.0143);

MVP

0.45

ClinPred

0.26

GERP RS

2.9

PromoterAI

-0.028

Neutral

(source)

Varity_R

0.26

Mutation Taster

=80/20

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over