15-52788962-T-C

Position:

• chr15-52788962-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004498.4(ONECUT1):​c.923A>G​(p.Tyr308Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ONECUT1 NM_004498.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.96

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ONECUT1	NM_004498.4	c.923A>G	p.Tyr308Cys	missense_variant	1/2	ENST00000305901.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ONECUT1	ENST00000305901.7	c.923A>G	p.Tyr308Cys	missense_variant	1/2	1	NM_004498.4	P1
ONECUT1	ENST00000570208.2	c.350-14A>G		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5
ONECUT1	ENST00000561401.3	n.50+2067A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jul 28, 2021

The c.923A>G (p.Y308C) 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 923, causing the tyrosine (Y) at amino acid position 308 to be replaced by a cysteine (C). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.6	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.011	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.58		Loss of ubiquitination at K306 (P = 0.0609);
MVP		0.81
MPC		1.7
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.74
gMVP		0.85

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: chr15-53081159;