Genetic Variant NM_004498.4:c.563G>T (chr15-52789322-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004498.4(ONECUT1):c.563G>T(p.Gly188Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,427,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G188D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ONECUT1
NM_004498.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.13

Publications

2 publications found

Variant links:

Genes affected

ONECUT1 (HGNC:8138): (one cut homeobox 1) This gene encodes a member of the Cut homeobox family of transcription factors. Expression of the encoded protein is enriched in the liver, where it stimulates transcription of liver-expressed genes, and antagonizes glucocorticoid-stimulated gene transcription. This gene may influence a variety of cellular processes including glucose metabolism, cell cycle regulation, and it may also be associated with cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

ONECUT1 Gene-Disease associations (from GenCC):

neonatal diabetes mellitus
Inheritance: AR Classification: STRONG Submitted by: G2P

ONECUT1 links:

ENSG00000301738 (HGNC:):

ENSG00000301738 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3054067).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004498.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ONECUT1	NM_004498.4	MANE Select	c.563G>T	p.Gly188Val	missense	Exon 1 of 2	NP_004489.1	Q9UBC0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ONECUT1	ENST00000305901.7	TSL:1 MANE Select	c.563G>T	p.Gly188Val	missense	Exon 1 of 2	ENSP00000302630.4	Q9UBC0
ONECUT1	ENST00000570208.2	TSL:5	n.74G>T		non_coding_transcript_exon	Exon 1 of 5	ENSP00000476168.1	U3KQR8
ONECUT1	ENST00000561401.3	TSL:3	n.50+1707G>T		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000899

AC:

AN:

222494

AF XY:

0.00000840

show subpopulations

Gnomad AFR exome

AF:

0.0000648

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1427156

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

705434

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000304

AC:

AN:

32862

American (AMR)

AF:

0.00

AC:

AN:

42028

Ashkenazi Jewish (ASJ)

AF:

0.0000421

AC:

AN:

23768

East Asian (EAS)

AF:

0.00

AC:

AN:

39340

South Asian (SAS)

AF:

0.00

AC:

AN:

80086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51756

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5590

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092874

Other (OTH)

AF:

0.00

AC:

AN:

58852

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

Eigen

Benign

-0.057

Eigen_PC

Benign

0.034

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.97

M_CAP

Benign

0.026

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.1

PhyloP100

4.1

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-4.2

REVEL

Benign

0.078

Sift

Uncertain

0.014

Sift4G

Uncertain

0.025

Polyphen

0.16

Vest4

0.54

MutPred

0.21

Loss of glycosylation at S185 (P = 0.1006)

MVP

0.69

MPC

1.1

ClinPred

0.97

GERP RS

4.4

Varity_R

0.58

gMVP

0.39

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over