chr19-1753736-C-T

Variant names:

• chr19-1753736-C-T
• rs1302854088
• NM_001080488.2:c.74C>T

Variant summary

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

The NM_001080488.2(ONECUT3):​c.74C>T​(p.Pro25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P25R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ONECUT3 NM_001080488.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.14
• Publications: 0 publications found

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

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=0.17539078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ONECUT3	NM_001080488.2	c.74C>T	p.Pro25Leu	missense_variant	Exon 1 of 2	ENST00000382349.5	NP_001073957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ONECUT3	ENST00000382349.5	c.74C>T	p.Pro25Leu	missense_variant	Exon 1 of 2	5	NM_001080488.2	ENSP00000371786.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 878738 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 409694

African (AFR) AF: 0.00 AC: 0 AN: 16628

American (AMR) AF: 0.00 AC: 0 AN: 2364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6404

East Asian (EAS) AF: 0.00 AC: 0 AN: 6422

South Asian (SAS) AF: 0.00 AC: 0 AN: 17686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1832

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 792230

Other (OTH) AF: 0.00 AC: 0 AN: 29900

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.067
Eigen_PC	Benign	-0.031
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.1
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.11
Sift	Benign	0.044	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.92	P
Vest4		0.079
MutPred		0.20		Gain of helix (P = 0.0143);
MVP		0.39
ClinPred		0.36	T
GERP RS		2.9
PromoterAI		-0.015	Neutral
Varity_R		0.25
Mutation Taster		=86/14	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: rs1302854088; hg19: chr19-1753735;