10-11948503-C-T

Position:

chr10-11948503-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_015542.4(UPF2):c.3040G>A(p.Val1014Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,611,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

UPF2
NM_015542.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.33

Variant links:

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]

UPF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05450663).

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UPF2	NM_015542.4 linkuse as main transcript	c.3040G>A	p.Val1014Ile	missense_variant	16/22	ENST00000357604.10	NP_056357.1	Q9HAU5
UPF2	NM_080599.3 linkuse as main transcript	c.3040G>A	p.Val1014Ile	missense_variant	16/22		NP_542166.1	Q9HAU5
UPF2	XM_047424986.1 linkuse as main transcript	c.3040G>A	p.Val1014Ile	missense_variant	16/21		XP_047280942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
UPF2	ENST00000357604.10 linkuse as main transcript	c.3040G>A	p.Val1014Ile	missense_variant	16/22	1	NM_015542.4	ENSP00000350221.5	Q9HAU5
UPF2	ENST00000356352.6 linkuse as main transcript	c.3040G>A	p.Val1014Ile	missense_variant	15/21	1		ENSP00000348708.2	Q9HAU5
UPF2	ENST00000397053.6 linkuse as main transcript	c.3040G>A	p.Val1014Ile	missense_variant	16/22	5		ENSP00000380244.2	Q9HAU5

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

247728

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134182

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000901

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1459820

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726262

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

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:

0.00000180

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000662

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 03, 2024

The c.3040G>A (p.V1014I) alteration is located in exon 16 (coding exon 15) of the UPF2 gene. This alteration results from a G to A substitution at nucleotide position 3040, causing the valine (V) at amino acid position 1014 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

Benign

0.072

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.027

T;T;T

Eigen

Benign

-0.21

Eigen_PC

Benign

0.014

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.90

.;.;D

M_CAP

Benign

0.0046

MetaRNN

Benign

0.055

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.16

N;N;N

REVEL

Benign

0.046

Sift

Benign

0.40

T;T;T

Sift4G

Benign

0.40

T;T;T

Polyphen

0.0020

B;B;B

Vest4

0.31

MVP

0.34

MPC

0.51

ClinPred

0.089

GERP RS

4.3

Varity_R

0.086

gMVP

0.049

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over