19-1753747-C-A

Position:

• chr19-1753747-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001080488.2(ONECUT3):​c.85C>A​(p.Arg29Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000127 in 868,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 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. R29H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ONECUT3 NM_001080488.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27

Genes affected

ONECUT3 (HGNC:13399): (one cut homeobox 3) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26248604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ONECUT3	NM_001080488.2	c.85C>A	p.Arg29Ser	missense_variant	1/2	ENST00000382349.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ONECUT3	ENST00000382349.5	c.85C>A	p.Arg29Ser	missense_variant	1/2	5	NM_001080488.2	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000127 AC: 11 AN: 868412 Hom.: 0 Cov.: 25 AF XY: 0.00000989 AC XY: 4 AN XY: 404288

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000140

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

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

May 09, 2023

The c.85C>A (p.R29S) alteration is located in exon 1 (coding exon 1) of the ONECUT3 gene. This alteration results from a C to A substitution at nucleotide position 85, causing the arginine (R) at amino acid position 29 to be replaced by a serine (S). 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Benign	0.025	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.076
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.12
Sift	Benign	0.047	D
Sift4G	Benign	0.49	T
Polyphen		0.98	D
Vest4		0.16
MutPred		0.32		Loss of MoRF binding (P = 0.015);
MVP		0.49
ClinPred		0.54	D
GERP RS		2.9
Varity_R		0.20

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

LitVar

Other links and lift over

dbSNP: rs2067900485; hg19: chr19-1753746;