chr10-11955489-T-A

Position:

• chr10-11955489-T-A

Variant summary

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

The NM_015542.4(UPF2):​c.2593A>T​(p.Asn865Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UPF2 NM_015542.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

Genes affected

UPF2 (HGNC:17854): (UPF2 regulator of nonsense mediated mRNA decay) This gene encodes a protein that is part of a post-splicing multiprotein complex involved in both mRNA nuclear export and mRNA surveillance. mRNA surveillance detects exported mRNAs with truncated open reading frames and initiates nonsense-mediated mRNA decay (NMD). When translation ends upstream from the last exon-exon junction, this triggers NMD to degrade mRNAs containing premature stop codons. This protein is located in the perinuclear area. It interacts with translation release factors and the proteins that are functional homologs of yeast Upf1p and Upf3p. Two splice variants have been found for this gene; both variants encode the same protein. [provided by RefSeq, Jul 2008]

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, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UPF2	NM_015542.4	c.2593A>T	p.Asn865Tyr	missense_variant	14/22	ENST00000357604.10
UPF2	NM_080599.3	c.2593A>T	p.Asn865Tyr	missense_variant	14/22
UPF2	XM_047424986.1	c.2593A>T	p.Asn865Tyr	missense_variant	14/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UPF2	ENST00000357604.10	c.2593A>T	p.Asn865Tyr	missense_variant	14/22	1	NM_015542.4	P1
UPF2	ENST00000356352.6	c.2593A>T	p.Asn865Tyr	missense_variant	13/21	1		P1
UPF2	ENST00000397053.6	c.2593A>T	p.Asn865Tyr	missense_variant	14/22	5		P1

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

Jan 19, 2024

The c.2593A>T (p.N865Y) alteration is located in exon 14 (coding exon 13) of the UPF2 gene. This alteration results from a A to T substitution at nucleotide position 2593, causing the asparagine (N) at amino acid position 865 to be replaced by a tyrosine (Y). 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	0.88
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;.;D
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	2.0	M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-6.2	D;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.033	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.91
MutPred		0.58		Loss of disorder (P = 0.0199);Loss of disorder (P = 0.0199);Loss of disorder (P = 0.0199);
MVP		0.81
MPC		1.8
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.79
gMVP		0.89

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: chr10-11997488;