2-158115161-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_173355.4(UPP2):c.241G>A(p.Glu81Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. E81G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UPP2 NM_173355.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18

Genes affected

UPP2 (HGNC:23061): (uridine phosphorylase 2) Enables deoxyuridine phosphorylase activity; identical protein binding activity; and uridine phosphorylase activity. Involved in dCMP catabolic process and uridine catabolic process. Located in type III intermediate filament. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UPP2	NM_173355.4	c.241G>A	p.Glu81Lys	missense_variant	3/7	ENST00000005756.5
UPP2	NM_001135098.2	c.412G>A	p.Glu138Lys	missense_variant	5/9
UPP2	XM_017003484.2	c.241G>A	p.Glu81Lys	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UPP2	ENST00000005756.5	c.241G>A	p.Glu81Lys	missense_variant	3/7	1	NM_173355.4	P1
UPP2	ENST00000605860.5	c.412G>A	p.Glu138Lys	missense_variant	6/10	5
UPP2	ENST00000460456.1	n.377-8588G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Feb 27, 2023

The c.412G>A (p.E138K) alteration is located in exon 5 (coding exon 5) of the UPP2 gene. This alteration results from a G to A substitution at nucleotide position 412, causing the glutamic acid (E) at amino acid position 138 to be replaced by a lysine (K). 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	0.27
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.095
Eigen_PC	Benign	0.019
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T;T
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.13	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
Sift4G	Uncertain	0.049	D;T
Polyphen		0.97	.;D
Vest4		0.58
MutPred		0.76		.;Gain of methylation at E81 (P = 0.0235);
MVP		0.92
MPC		0.44
ClinPred		0.98	D
GERP RS		3.0
Varity_R		0.37
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr2-158971673;