Variant X-119834990-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP3BS2

The NM_080632.3(UPF3B):c.1340G>A(p.Arg447Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000073 in 1,096,166 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000073 ( 0 hom. 4 hem. )

Consequence

UPF3B
NM_080632.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.30

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a mutagenesis_site Abolishes NMD; when associated with E-449 and E-451. (size 0) in uniprot entity REN3B_HUMAN

PP3

MetaRNN computational evidence supports a deleterious effect, 0.787

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF3B	NM_080632.3 link	c.1340G>A	p.Arg447Gln	missense_variant	Exon 11 of 11	ENST00000276201.7	NP_542199.1	Q9BZI7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPF3B	ENST00000276201.7 link	c.1340G>A	p.Arg447Gln	missense_variant	Exon 11 of 11	1	NM_080632.3	ENSP00000276201.3		Q9BZI7-1
UPF3B	ENST00000345865.6 link	c.1301G>A	p.Arg434Gln	missense_variant	Exon 10 of 10	1		ENSP00000245418.2		Q9BZI7-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000730

AC:

AN:

1096166

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

362034

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:

0.00000714

Gnomad4 OTH exome

AF:

0.0000435

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Syndromic X-linked intellectual disability 14

Uncertain:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 447 of the UPF3B protein (p.Arg447Gln). 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. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt UPF3B protein function with a positive 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.14

T;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.79

D;D

MetaSVM

Uncertain

0.55

MutationAssessor

Pathogenic

3.0

M;.

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.5

N;N

REVEL

Uncertain

0.61

Sift

Uncertain

0.017

D;D

Sift4G

Uncertain

0.042

D;D

Polyphen

1.0

D;D

Vest4

0.68

MutPred

0.42

Loss of MoRF binding (P = 0.0145);.;

MVP

0.90

MPC

1.3

ClinPred

0.99

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.78

gMVP

0.27

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over