X-119834909-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_080632.3(UPF3B):c.1421T>A(p.Ile474Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: UPF3B NM_080632.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06861526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UPF3B	NM_080632.3	c.1421T>A	p.Ile474Asn	missense_variant	11/11	ENST00000276201.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UPF3B	ENST00000276201.7	c.1421T>A	p.Ile474Asn	missense_variant	11/11	1	NM_080632.3	A1
UPF3B	ENST00000345865.6	c.1382T>A	p.Ile461Asn	missense_variant	10/10	1		P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 14, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.1421T>A (p.I474N) alteration is located in coding exon 11 of the UPF3B gene. This alteration results from a T to A substitution at nucleotide position 1421, causing the isoleucine (I) at amino acid position 474 to be replaced by an asparagine (N). The alteration is not observed in healthy cohorts:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the UPF3B c.1421T>A alteration was not observed, with coverage at this site. The altered amino acid is not conserved throughout evolution:_x000D_ _x000D_ The p.I474 amino acid is not conserved in available vertebrate species. The alteration is predicted benign by in silico models:_x000D_ _x000D_ The p.I474N alteration is predicted to be benign by Polyphen and tolerated by SIFT in silico analyses. 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	Uncertain	0.41
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	20
Dann	Benign	0.93
DEOGEN2	Benign	0.018	T;.
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.069	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	0.86	N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.52	N;N
REVEL	Benign	0.23
Sift	Benign	0.48	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.0010	B;B
Vest4		0.23
MutPred		0.13		Loss of catalytic residue at I474 (P = 0.0585);.;
MVP		0.52
MPC		0.92
ClinPred		0.27	T
GERP RS		4.0
Varity_R		0.35
gMVP		0.078

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2056076026; hg19: chrX-118968872;