X-119837773-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_080632.3(UPF3B):c.1286A>G(p.Asp429Gly) 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: 22)
• Consequence: UPF3B NM_080632.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.30

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UPF3B	NM_080632.3	c.1286A>G	p.Asp429Gly	missense_variant	10/11	ENST00000276201.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UPF3B	ENST00000276201.7	c.1286A>G	p.Asp429Gly	missense_variant	10/11	1	NM_080632.3	A1
UPF3B	ENST00000345865.6	c.1247A>G	p.Asp416Gly	missense_variant	9/10	1		P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 09, 2018

The D429G variant in the UPF3B gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The D429G variant is not observed in large population cohorts (Lek et al., 2016). The D429G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret D429G as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Uncertain	0.042	D
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.039	D;D
Polyphen		0.99	D;D
Vest4		0.66
MutPred		0.33		Loss of helix (P = 0.0237);.;
MVP		0.84
MPC		1.4
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.70
gMVP		0.085

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1064794658; hg19: chrX-118971736;