Variant X-119841205-TTTTC-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_080632.3(UPF3B):c.674_677delGAAA(p.Arg225LysfsTer22) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000505 in 1,188,318 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000037 ( 0 hom. 0 hem. )

Consequence

UPF3B
NM_080632.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 5.81

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 Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant X-119841205-TTTTC-T is Pathogenic according to our data. Variant chrX-119841205-TTTTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 198608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF3B	NM_080632.3 link	c.674_677delGAAA	p.Arg225LysfsTer22	frameshift_variant	Exon 7 of 11	ENST00000276201.7	NP_542199.1	Q9BZI7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UPF3B	ENST00000276201.7 link	c.674_677delGAAA	p.Arg225LysfsTer22	frameshift_variant	Exon 7 of 11	1	NM_080632.3	ENSP00000276201.3	Q9BZI7-1
UPF3B	ENST00000345865.6 link	c.674_677delGAAA	p.Arg225LysfsTer22	frameshift_variant	Exon 7 of 10	1		ENSP00000245418.2	Q9BZI7-2
UPF3B	ENST00000478840.1 link	n.262_265delGAAA		non_coding_transcript_exon_variant	Exon 4 of 6	3

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111417

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33587

show subpopulations

Gnomad AFR

AF:

0.0000653

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000371

AC:

AN:

1076901

Hom.:

AF XY:

0.00

AC XY:

AN XY:

344727

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000332

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000364

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000180

AC:

AN:

111417

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33587

show subpopulations

Gnomad4 AFR

AF:

0.0000653

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Syndromic X-linked intellectual disability 14

Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 15, 2024	This sequence change creates a premature translational stop signal (p.Arg225Lysfs22) in the UPF3B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in UPF3B are known to be pathogenic (PMID: 17704778, 19238151). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with UPF3B-related conditions (PMID: 17704778). It has also been observed to segregate with disease in related individuals. This variant is also known as 674_677delGAAA and/or R225fs20. ClinVar contains an entry for this variant (Variation ID: 198608). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	Feb 10, 2020	The p.Arg225Lysfs22 variant in the UPF3B gene has been reported de novo in 1 individual and maternally inherited in 4 additional unrelated individuals (GeneDx, personal communication, January 17, 2020; Tarpey et al., 2007). In one family the variant co-segregated with disease between siblings. All of these individuals were hemizygous males who presented features consistent with UPF3B-associated intellectual disability disorder. The p.Arg225Lysfs22 variant results in a 4 bp deletion, which causes a shift in the protein reading frame, leading to a premature termination codon 22 amino acids downstream. Hemizygous loss of function is an established mechanism of disease for the UPF3B gene.The variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg225Lysfs*22 variant as pathogenic for X-linked UPF3B-associated intellectual disability disorder based on the information above. [ACMG evidence codes used: PVS1; PS2_supporting; PS4_supporting; PM2_supporting] -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 23, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with intellectual developmental disorder, X-linked syndromic 14 (MIM#300676). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes, 0 hemizygotes). (SP) 0701 - Many other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2022	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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17704778, 26012578, 19377476, 24665081) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 02, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2019	- -

UPF3B-associated intellectual disability

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpreted as Pathogenic and reported on 09-10-2020 by Lab or GTR ID Stanford Children's Hospital. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over