rs1064794254

Positions:

• chrX-119841184-CCT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_080632.3(UPF3B):​c.697_698del​(p.Arg233GlufsTer32) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: UPF3B NM_080632.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.86

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-119841184-CCT-C is Pathogenic according to our data. Variant chrX-119841184-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 420043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UPF3B	NM_080632.3	c.697_698del	p.Arg233GlufsTer32	frameshift_variant	7/11	ENST00000276201.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UPF3B	ENST00000276201.7	c.697_698del	p.Arg233GlufsTer32	frameshift_variant	7/11	1	NM_080632.3	A1
UPF3B	ENST00000345865.6	c.697_698del	p.Arg233GlufsTer32	frameshift_variant	7/10	1		P4
UPF3B	ENST00000478840.1	n.285_286del		non_coding_transcript_exon_variant	4/6	3

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Syndromic X-linked intellectual disability 14 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing;provider interpretation

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Mar 28, 2017

This 2 year old male with global developmental delays, autism spectrum disorder, large stature, and macrocephaly was found to carry a maternally inherited frameshift variant in the UPF3B gene. The patient also has dolicocephaly, wide nasal bridge, epicanthal folds, full lips, and a wide mouth. The patient's mother is unaffected. The patient's maternal great-uncle was found to harbor the same variant; he has an intellectual disability and reported macrocephaly. The c.697_698delAG variant in the UPF3B gene has been reported previously in two brothers, both with developmental delay and renal dysplasia, and one also with macrocephaly (Lynch et al., 2012). The c.697_698delAG variant causes a frameshift and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is absent from population databases. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 15, 2019

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22609145) -

Computational scores

Source: dbNSFP v4.3

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: rs1064794254; hg19: chrX-118975147;