NM_004852.3:c.130G>A

Variant names:

• chr18-57435846-G-A
• rs201085296
• NM_004852.3:c.130G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004852.3(ONECUT2):​c.130G>A​(p.Gly44Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,002,774 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (3 hom.)
• Consequence: ONECUT2 NM_004852.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0480
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028811693).
• BP6: Variant 18-57435846-G-A is Benign according to our data. Variant chr18-57435846-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2274640.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 113 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ONECUT2	NM_004852.3	c.130G>A	p.Gly44Ser	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.130G>A	p.Gly44Ser	missense_variant	Exon 1 of 2	1	NM_004852.3	ENSP00000419185.2

Frequencies

GnomAD3 genomes AF: 0.000777 AC: 113 AN: 145480 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000136

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000633

Gnomad FIN AF: 0.00325

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00100

GnomAD2 exomes AF: 0.0186 AC: 83 AN: 4454 AF XY: 0.0225

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00908

Gnomad NFE exome AF: 0.284

Gnomad OTH exome AF: 0.100

GnomAD4 exome AF: 0.00105 AC: 896 AN: 857214 Hom.: 3 Cov.: 31 AF XY: 0.00107 AC XY: 427 AN XY: 400406

African (AFR) AF: 0.0000626 AC: 1 AN: 15978

American (AMR) AF: 0.00 AC: 0 AN: 1326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5322

East Asian (EAS) AF: 0.00 AC: 0 AN: 4138

South Asian (SAS) AF: 0.00176 AC: 31 AN: 17588

European-Finnish (FIN) AF: 0.00943 AC: 73 AN: 7744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1680

European-Non Finnish (NFE) AF: 0.000997 AC: 773 AN: 775342

Other (OTH) AF: 0.000641 AC: 18 AN: 28096

GnomAD4 genome AF: 0.000776 AC: 113 AN: 145560 Hom.: 0 Cov.: 31 AF XY: 0.000848 AC XY: 60 AN XY: 70778

African (AFR) AF: 0.000221 AC: 9 AN: 40672

American (AMR) AF: 0.000136 AC: 2 AN: 14702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3386

East Asian (EAS) AF: 0.00 AC: 0 AN: 4970

South Asian (SAS) AF: 0.000634 AC: 3 AN: 4732

European-Finnish (FIN) AF: 0.00325 AC: 27 AN: 8300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.00107 AC: 70 AN: 65602

Other (OTH) AF: 0.000993 AC: 2 AN: 2014

Alfa AF: 0.000736 Hom.: 0

Bravo AF: 0.000495

ExAC AF: 0.0372 AC: 70

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 17, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.048
PrimateAI	Pathogenic	0.81	D
REVEL	Benign	0.064
Sift4G	Benign	0.16	T
Polyphen		0.038	B
Vest4		0.080
MutPred		0.24		Gain of glycosylation at G44 (P = 9e-04);
MPC		1.6
ClinPred		0.067	T
GERP RS		1.9
PromoterAI		-0.031	Neutral
Varity_R		0.10
gMVP		0.40
Mutation Taster		=89/11	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: rs201085296; hg19: chr18-55103078;