NM_004498.4:c.926G>A

Variant names:

• chr15-52788959-C-T
• rs1390509365
• NM_004498.4:c.926G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004498.4(ONECUT1):​c.926G>A​(p.Ser309Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,216 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S309T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ONECUT1 NM_004498.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.02
• Publications: 0 publications found

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

ENSG00000301738 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.926G>A	p.Ser309Asn	missense	Exon 1 of 2	NP_004489.1	Q9UBC0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ONECUT1	ENST00000305901.7	TSL:1 MANE Select	c.926G>A	p.Ser309Asn	missense	Exon 1 of 2	ENSP00000302630.4	Q9UBC0
	ONECUT1	ENST00000561401.3	TSL:3	n.50+2070G>A		intron	N/A
	ONECUT1	ENST00000570208.2	TSL:5	n.349-11G>A		intron	N/A	ENSP00000476168.1	U3KQR8

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.5	L
PhyloP100		6.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.24
Sift	Benign	0.10	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.66	P
Vest4		0.65
MutPred		0.39		Loss of phosphorylation at S309 (P = 0.0614)
MVP		0.70
MPC		1.3
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.57
gMVP		0.80

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

Other links and lift over

dbSNP: rs1390509365; hg19: chr15-53081156;