10-11952212-G-A

Position:

• chr10-11952212-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_015542.4(UPF2):​c.2888C>T​(p.Thr963Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,459,338 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: 0.0000069 (0 hom.)
• Consequence: UPF2 NM_015542.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.52

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 Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UPF2	NM_015542.4	c.2888C>T	p.Thr963Ile	missense_variant	15/22	ENST00000357604.10
UPF2	NM_080599.3	c.2888C>T	p.Thr963Ile	missense_variant	15/22
UPF2	XM_047424986.1	c.2888C>T	p.Thr963Ile	missense_variant	15/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UPF2	ENST00000357604.10	c.2888C>T	p.Thr963Ile	missense_variant	15/22	1	NM_015542.4	P1
UPF2	ENST00000356352.6	c.2888C>T	p.Thr963Ile	missense_variant	14/21	1		P1
UPF2	ENST00000397053.6	c.2888C>T	p.Thr963Ile	missense_variant	15/22	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1459338 Hom.: 0 Cov.: 31 AF XY: 0.00000827 AC XY: 6 AN XY: 725732

Gnomad4 AFR exome AF: 0.000150

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: 0.00

Gnomad4 OTH exome AF: 0.0000664

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Oct 27, 2022

The c.2888C>T (p.T963I) alteration is located in exon 15 (coding exon 14) of the UPF2 gene. This alteration results from a C to T substitution at nucleotide position 2888, causing the threonine (T) at amino acid position 963 to be replaced by an isoleucine (I). 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	0.61
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;.;D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.015	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.75
MutPred		0.66		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP		0.66
MPC		1.1
ClinPred		0.98	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1833084419; hg19: chr10-11994211;