Genetic Variant ONECUT2:p.Gly34Trp (chr18-57435816-G-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_004852.3(ONECUT2):c.100G>T(p.Gly34Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000619 in 1,130,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000030 ( 0 hom. )

Consequence

ONECUT2
NM_004852.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.11

Publications

1 publications found

Variant links:

Genes affected

ONECUT2 (HGNC:8139): (one cut homeobox 2) This gene encodes a member of the onecut family of transcription factors, which are characterized by a cut domain and an atypical homeodomain. The protein binds to specific DNA sequences and stimulates expression of target genes, including genes involved in melanocyte and hepatocyte differentiation. [provided by RefSeq, Jul 2008]

ONECUT2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.35848927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ONECUT2	NM_004852.3 link	c.100G>T	p.Gly34Trp	missense_variant	Exon 1 of 2	ENST00000491143.3	NP_004843.2	O95948

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ONECUT2	ENST00000491143.3 link	c.100G>T	p.Gly34Trp	missense_variant	Exon 1 of 2	1	NM_004852.3	ENSP00000419185.2		O95948

Frequencies

GnomAD3 genomes

AF:

0.0000273

AC:

AN:

146266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000136

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.0000152

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000146

AC:

AN:

137254

AF XY:

0.0000126

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000298

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000305

AC:

AN:

984476

Hom.:

Cov.:

AF XY:

0.00000419

AC XY:

AN XY:

476944

show subpopulations

African (AFR)

AF:

0.0000529

AC:

AN:

18906

American (AMR)

AF:

0.00

AC:

AN:

15114

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10572

East Asian (EAS)

AF:

0.00

AC:

AN:

8562

South Asian (SAS)

AF:

0.00

AC:

AN:

34664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21772

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2308

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

839678

Other (OTH)

AF:

0.0000304

AC:

AN:

32900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000273

AC:

AN:

146266

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

71102

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40828

American (AMR)

AF:

0.000136

AC:

AN:

14736

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3390

East Asian (EAS)

AF:

0.00

AC:

AN:

5076

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8362

Middle Eastern (MID)

AF:

0.00321

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000152

AC:

AN:

65842

Other (OTH)

AF:

0.00

AC:

AN:

2012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000204

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000876

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 16, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.100G>T (p.G34W) alteration is located in exon 1 (coding exon 1) of the ONECUT2 gene. This alteration results from a G to T substitution at nucleotide position 100, causing the glycine (G) at amino acid position 34 to be replaced by a tryptophan (W). 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

Uncertain

0.46

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

Eigen

Benign

0.15

Eigen_PC

Benign

0.098

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.44

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.36

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.3

PhyloP100

5.1

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

0.14

REVEL

Benign

0.21

Sift

Benign

0.036

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.43

MutPred

0.38

Loss of disorder (P = 0.0927);

MVP

0.42

MPC

1.9

ClinPred

0.75

GERP RS

1.9

PromoterAI

-0.014

Neutral

(source)

Varity_R

0.34

gMVP

0.35

Mutation Taster

=75/25

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

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18-57435816-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over