19-4910973-C-T

Variant names:

• chr19-4910973-C-T
• rs763928060
• NM_001048201.3:c.88C>T

Variant summary

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

The NM_001048201.3(UHRF1):​c.88C>T​(p.Arg30Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/16 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. R30G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: UHRF1 NM_001048201.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.293
• Publications: 1 publications found

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]

ARRDC5 (HGNC:31407): (arrestin domain containing 5) Predicted to enable ubiquitin ligase-substrate adaptor activity and ubiquitin protein ligase binding activity. Predicted to be involved in protein transport. Predicted to be active in cytoplasm. [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=0.13938448).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001048201.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UHRF1	NM_001048201.3	MANE Select	c.88C>T	p.Arg30Trp	missense	Exon 2 of 17	NP_001041666.1	Q96T88-1
	UHRF1	NM_013282.5		c.127C>T	p.Arg43Trp	missense	Exon 1 of 16	NP_037414.3
	UHRF1	NM_001290050.2		c.88C>T	p.Arg30Trp	missense	Exon 2 of 17	NP_001276979.1	Q96T88-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UHRF1	ENST00000650932.1	MANE Select	c.88C>T	p.Arg30Trp	missense	Exon 2 of 17	ENSP00000498698.1	Q96T88-1
	UHRF1	ENST00000620565.4	TSL:1	c.280C>T	p.Arg94Trp	missense	Exon 2 of 17	ENSP00000478171.1	A0A087WTW0
	UHRF1	ENST00000622802.4	TSL:1	c.127C>T	p.Arg43Trp	missense	Exon 1 of 16	ENSP00000479617.1	A0A087WVR3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248266 AF XY: 0.00000742

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: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460840 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 726732

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111344

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.087	N
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.29
PrimateAI	Benign	0.26	T
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.32
MutPred		0.45		Gain of catalytic residue at L28 (P = 0.0084)
MVP		0.29
ClinPred		0.48	T
GERP RS		-4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.78

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: rs763928060; hg19: chr19-4910985;