chrX-119843293-A-C

Position:

• chrX-119843293-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_080632.3(UPF3B):​c.478T>G​(p.Tyr160Asp) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: UPF3B NM_080632.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.89

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853
• PP5: Variant X-119843293-A-C is Pathogenic according to our data. Variant chrX-119843293-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 11401.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UPF3B	NM_080632.3	c.478T>G	p.Tyr160Asp	missense_variant	5/11	ENST00000276201.7	NP_542199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UPF3B	ENST00000276201.7	c.478T>G	p.Tyr160Asp	missense_variant	5/11	1	NM_080632.3	ENSP00000276201.3
UPF3B	ENST00000345865.6	c.478T>G	p.Tyr160Asp	missense_variant	5/10	1		ENSP00000245418.2
UPF3B	ENST00000478840.1	n.66T>G		non_coding_transcript_exon_variant	2/6	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Syndromic X-linked intellectual disability 14 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.9	H;H;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-8.7	D;D;.
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;P;.
Vest4		0.96
MutPred		0.54		Loss of phosphorylation at Y160 (P = 0.0106);Loss of phosphorylation at Y160 (P = 0.0106);Loss of phosphorylation at Y160 (P = 0.0106);
MVP		0.98
MPC		1.7
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.99
gMVP		0.96

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

Other links and lift over

dbSNP: rs122468182; hg19: chrX-118977256;