chr18-57435832-G-A

Variant names:

• chr18-57435832-G-A
• rs1404257944
• NM_004852.3:c.116G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004852.3(ONECUT2):​c.116G>A​(p.Gly39Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000105 in 948,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G39C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: ONECUT2 NM_004852.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.15
• Publications: 0 publications found

Genes affected

ONECUT2 (HGNC:8139): (one cut homeobox 2) This gene encodes a member of the onecut family of transcription factors, which are characterized by a cut domain and an atypical homeodomain. The protein binds to specific DNA sequences and stimulates expression of target genes, including genes involved in melanocyte and hepatocyte differentiation. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0801546).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ONECUT2	NM_004852.3	c.116G>A	p.Gly39Asp	missense_variant	Exon 1 of 2	ENST00000491143.3	NP_004843.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ONECUT2	ENST00000491143.3	c.116G>A	p.Gly39Asp	missense_variant	Exon 1 of 2	1	NM_004852.3	ENSP00000419185.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000105 AC: 1 AN: 948926 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 455688

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

African (AFR) AF: 0.0000557 AC: 1 AN: 17950

American (AMR) AF: 0.00 AC: 0 AN: 10218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9230

East Asian (EAS) AF: 0.00 AC: 0 AN: 7562

South Asian (SAS) AF: 0.00 AC: 0 AN: 30562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1972

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 820900

Other (OTH) AF: 0.00 AC: 0 AN: 31320

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.116G>A (p.G39D) alteration is located in exon 1 (coding exon 1) of the ONECUT2 gene. This alteration results from a G to A substitution at nucleotide position 116, causing the glycine (G) at amino acid position 39 to be replaced by an aspartic acid (D). 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	0.21
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.43	T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.2
PrimateAI	Pathogenic	0.86	D
REVEL	Benign	0.16
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.16		Loss of catalytic residue at P35 (P = 0.074);
MVP		0.32
MPC		0.90
ClinPred		0.11	T
GERP RS		1.9
PromoterAI		-0.044	Neutral
Varity_R		0.093
gMVP		0.26
Mutation Taster		=92/8	polymorphism

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: rs1404257944; hg19: chr18-55103064;