X-119837794-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_080632.3(UPF3B):c.1265A>G(p.Lys422Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,208,775 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000016 ( 0 hom. 6 hem. )

Consequence

UPF3B
NM_080632.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.30

Variant links:

Genes affected

UPF3B (HGNC:20439): (UPF3B 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. The encoded protein is one of two functional homologs to yeast Upf3p. 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 binds to the mRNA and remains bound after nuclear export, acting as a nucleocytoplasmic shuttling protein. It forms with Y14 a complex that binds specifically 20 nt upstream of exon-exon junctions. This gene is located on the long arm of chromosome X. Two splice variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

UPF3B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.33740938).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UPF3B	NM_080632.3 linkuse as main transcript	c.1265A>G	p.Lys422Arg	missense_variant	10/11	ENST00000276201.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UPF3B	ENST00000276201.7 linkuse as main transcript	c.1265A>G	p.Lys422Arg	missense_variant	10/11	1	NM_080632.3	A1	Q9BZI7-1
UPF3B	ENST00000345865.6 linkuse as main transcript	c.1226A>G	p.Lys409Arg	missense_variant	9/10	1		P4	Q9BZI7-2

Frequencies

GnomAD3 genomes

AF:

0.00000897

AC:

AN:

111543

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

33725

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1097232

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

362758

show subpopulations

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:

0.0000202

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.00000897

AC:

AN:

111543

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

33725

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Syndromic X-linked intellectual disability 14

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 10, 2023

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 422 of the UPF3B protein (p.Lys422Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with UPF3B-related conditions. ClinVar contains an entry for this variant (Variation ID: 1763970). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt UPF3B protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 05, 2019

The p.K422R variant (also known as c.1265A>G), located in coding exon 10 of the UPF3B gene, results from an A to G substitution at nucleotide position 1265. The lysine at codon 422 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Benign

-0.34

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.029

T;.

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.79

T;T

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.34

T;T

MetaSVM

Uncertain

-0.15

MutationAssessor

Uncertain

2.6

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.87

N;N

REVEL

Uncertain

0.38

Sift

Benign

0.30

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.70

P;P

Vest4

0.41

MutPred

0.20

Loss of ubiquitination at K422 (P = 0.0107);.;

MVP

0.78

MPC

1.0

ClinPred

0.84

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.41

gMVP

0.032

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