15-52789155-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004498.4(ONECUT1):c.730A>G(p.Ile244Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ONECUT1 NM_004498.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.910

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18566188).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ONECUT1	NM_004498.4	c.730A>G	p.Ile244Val	missense_variant	1/2	ENST00000305901.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ONECUT1	ENST00000305901.7	c.730A>G	p.Ile244Val	missense_variant	1/2	1	NM_004498.4	P1
ONECUT1	ENST00000570208.2	c.244A>G	p.Ile82Val	missense_variant, NMD_transcript_variant	1/5	5
ONECUT1	ENST00000561401.3	n.50+1874A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443312 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 717614

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.730A>G (p.I244V) alteration is located in exon 1 (coding exon 1) of the ONECUT1 gene. This alteration results from a A to G substitution at nucleotide position 730, causing the isoleucine (I) at amino acid position 244 to be replaced by a valine (V). 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	0.096
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	20
Dann	Benign	0.94
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.85	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.092
Sift	Benign	0.23	T
Sift4G	Benign	0.43	T
Polyphen		0.062	B
Vest4		0.43
MutPred		0.12		Loss of glycosylation at P249 (P = 0.2067);
MVP		0.46
MPC		0.54
ClinPred		0.16	T
GERP RS		3.6
Varity_R		0.10
gMVP		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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-53081352;