18-57435774-A-G

Variant names:

• chr18-57435774-A-G
• rs369785174
• NM_004852.3:c.58A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004852.3(ONECUT2):​c.58A>G​(p.Met20Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000775 in 1,264,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. M20T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000083 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: ONECUT2 NM_004852.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.64
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13169274).
• BS2: High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ONECUT2	NM_004852.3	c.58A>G	p.Met20Val	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.58A>G	p.Met20Val	missense_variant	Exon 1 of 2	1	NM_004852.3	ENSP00000419185.2

Frequencies

GnomAD3 genomes AF: 0.0000829 AC: 12 AN: 144752 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000685

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000153

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000148 AC: 27 AN: 182318 AF XY: 0.000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000316

Gnomad OTH exome AF: 0.000251

GnomAD4 exome AF: 0.0000768 AC: 86 AN: 1119286 Hom.: 0 Cov.: 32 AF XY: 0.0000847 AC XY: 47 AN XY: 554646

African (AFR) AF: 0.0000462 AC: 1 AN: 21638

American (AMR) AF: 0.0000721 AC: 2 AN: 27722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14390

East Asian (EAS) AF: 0.00 AC: 0 AN: 9356

South Asian (SAS) AF: 0.0000142 AC: 1 AN: 70448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28726

Middle Eastern (MID) AF: 0.00116 AC: 4 AN: 3456

European-Non Finnish (NFE) AF: 0.0000807 AC: 73 AN: 904920

Other (OTH) AF: 0.000129 AC: 5 AN: 38630

GnomAD4 genome AF: 0.0000829 AC: 12 AN: 144752 Hom.: 0 Cov.: 30 AF XY: 0.0000995 AC XY: 7 AN XY: 70344

African (AFR) AF: 0.00 AC: 0 AN: 40392

American (AMR) AF: 0.0000685 AC: 1 AN: 14606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3380

East Asian (EAS) AF: 0.00 AC: 0 AN: 4852

South Asian (SAS) AF: 0.00 AC: 0 AN: 4578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8194

Middle Eastern (MID) AF: 0.00321 AC: 1 AN: 312

European-Non Finnish (NFE) AF: 0.000153 AC: 10 AN: 65526

Other (OTH) AF: 0.00 AC: 0 AN: 2006

Alfa AF: 0.000117 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000396 AC: 3

ExAC AF: 0.000181 AC: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.58A>G (p.M20V) alteration is located in exon 1 (coding exon 1) of the ONECUT2 gene. This alteration results from a A to G substitution at nucleotide position 58, causing the methionine (M) at amino acid position 20 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	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.50	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.6
PrimateAI	Pathogenic	0.86	D
REVEL	Benign	0.27
Sift4G	Uncertain	0.052	T
Polyphen		0.047	B
Vest4		0.46
MVP		0.78
MPC		0.95
ClinPred		0.15	T
GERP RS		1.9
PromoterAI		-0.098	Neutral
Varity_R		0.88
gMVP		0.46
Mutation Taster		=65/35	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: rs369785174; hg19: chr18-55103006;