9-6413602-G-T

Position:

• chr9-6413602-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_152896.3(UHRF2):​c.112G>T​(p.Val38Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: UHRF2 NM_152896.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.92

Genes affected

UHRF2 (HGNC:12557): (ubiquitin like with PHD and ring finger domains 2) This gene encodes a nuclear protein which is involved in cell-cycle regulation. The encoded protein is a ubiquitin-ligase capable of ubiquinating PCNP (PEST-containing nuclear protein), and together they may play a role in tumorigenesis. The encoded protein contains an NIRF_N domain, a PHD finger, a set- and ring-associated (SRA) domain, and a RING finger domain and several of these domains have been shown to be essential for the regulation of cell proliferation. This protein may also have a role in intranuclear degradation of polyglutamine aggregates. Alternative splicing results in multiple transcript variants some of which are non-protein coding. [provided by RefSeq, Feb 2012]

UHRF2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UHRF2	NM_152896.3	c.112G>T	p.Val38Leu	missense_variant	1/16	ENST00000276893.10	NP_690856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UHRF2	ENST00000276893.10	c.112G>T	p.Val38Leu	missense_variant	1/16	1	NM_152896.3	ENSP00000276893.5
UHRF2	ENST00000468435.6	n.112G>T		non_coding_transcript_exon_variant	1/17	1		ENSP00000434182.1
UHRF2	ENST00000381373.3	c.112G>T	p.Val38Leu	missense_variant	1/3	3		ENSP00000370778.3
UHRF2	ENST00000469298.5	n.283G>T		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448220 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 720420

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

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

Jan 20, 2023

The c.112G>T (p.V38L) alteration is located in exon 1 (coding exon 1) of the UHRF2 gene. This alteration results from a G to T substitution at nucleotide position 112, causing the valine (V) at amino acid position 38 to be replaced by a leucine (L). 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	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.032	D;D
Polyphen		0.99	D;.
Vest4		0.72
MutPred		0.55		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.75
MPC		0.63
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.39
gMVP		0.70

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: chr9-6413602;