19-4944208-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001048201.3(UHRF1):c.1150G>A(p.Ala384Thr) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UHRF1 NM_001048201.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.11

Genes affected

UHRF1 (HGNC:12556): (ubiquitin like with PHD and ring finger domains 1) This gene encodes a member of a subfamily of RING-finger type E3 ubiquitin ligases. The protein binds to specific DNA sequences, and recruits a histone deacetylase to regulate gene expression. Its expression peaks at late G1 phase and continues during G2 and M phases of the cell cycle. It plays a major role in the G1/S transition by regulating topoisomerase IIalpha and retinoblastoma gene expression, and functions in the p53-dependent DNA damage checkpoint. It is regarded as a hub protein for the integration of epigenetic information. This gene is up-regulated in various cancers, and it is therefore considered to be a therapeutic target. Multiple transcript variants encoding different isoforms have been found for this gene. A related pseudogene exists on chromosome 12. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, UHRF1
• BP4: Computational evidence support a benign effect (MetaRNN=0.18035626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UHRF1	NM_001048201.3	c.1150G>A	p.Ala384Thr	missense_variant	8/17	ENST00000650932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UHRF1	ENST00000650932.1	c.1150G>A	p.Ala384Thr	missense_variant	8/17		NM_001048201.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Aug 19, 2023

The c.1189G>A (p.A397T) alteration is located in exon 7 (coding exon 7) of the UHRF1 gene. This alteration results from a G to A substitution at nucleotide position 1189, causing the alanine (A) at amino acid position 397 to be replaced by a threonine (T). 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	0.16
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;T;T;T;.;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.88	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.4	L;.;.;L;L;.;L
PrimateAI	Benign	0.42	T
Sift4G	Benign	0.25	T;T;T;T;T;T;T
Polyphen		0.97	D;.;.;D;D;.;D
Vest4		0.23
MutPred		0.21		Gain of phosphorylation at A384 (P = 0.0241);.;.;Gain of phosphorylation at A384 (P = 0.0241);Gain of phosphorylation at A384 (P = 0.0241);.;Gain of phosphorylation at A384 (P = 0.0241);
MVP		0.41
ClinPred		0.65	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-4944220;