15-52789643-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004498.4(ONECUT1):c.242G>A(p.Gly81Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,550,464 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: ONECUT1 NM_004498.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.04

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3155129).
• BS2: High AC in GnomAd at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ONECUT1	NM_004498.4	c.242G>A	p.Gly81Asp	missense_variant	1/2	ENST00000305901.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ONECUT1	ENST00000305901.7	c.242G>A	p.Gly81Asp	missense_variant	1/2	1	NM_004498.4	P1
ONECUT1	ENST00000561401.3	n.50+1386G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 152028 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000233 AC: 45 AN: 193526 Hom.: 0 AF XY: 0.000301 AC XY: 31 AN XY: 103058

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000698

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000127

Gnomad SAS exome AF: 0.000449

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000142 AC: 199 AN: 1398318 Hom.: 1 Cov.: 31 AF XY: 0.000158 AC XY: 109 AN XY: 689436

Gnomad4 AFR exome AF: 0.000128

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.000137

Gnomad4 EAS exome AF: 0.000106

Gnomad4 SAS exome AF: 0.000473

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000104

Gnomad4 OTH exome AF: 0.000261

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74382

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.000121

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000350 AC: 3

ExAC AF: 0.000331 AC: 40

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal dominant polycystic liver disease Uncertain:1

Uncertain significance, no assertion criteria provided

research

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Sep 01, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.82	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.12
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.61
MVP		0.70
MPC		1.3
ClinPred		0.12	T
GERP RS		3.2
Varity_R		0.39
gMVP		0.56

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

Other links and lift over

dbSNP: rs142641519; hg19: chr15-53081840;