rs794727881

Variant names:

• chrX-119841205-TTTTC-T
• rs794727881
• NM_080632.3:c.674_677delGAAA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 5.81
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• syndromic X-linked intellectual disability 14

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability with marfanoid habitus

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 198608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080632.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UPF3B	NM_080632.3	MANE Select	c.674_677delGAAA	p.Arg225LysfsTer22	frameshift	Exon 7 of 11	NP_542199.1
	UPF3B	NM_023010.4		c.674_677delGAAA	p.Arg225LysfsTer22	frameshift	Exon 7 of 10	NP_075386.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UPF3B	ENST00000276201.7	TSL:1 MANE Select	c.674_677delGAAA	p.Arg225LysfsTer22	frameshift	Exon 7 of 11	ENSP00000276201.3
	UPF3B	ENST00000345865.6	TSL:1	c.674_677delGAAA	p.Arg225LysfsTer22	frameshift	Exon 7 of 10	ENSP00000245418.2
	UPF3B	ENST00000478840.1	TSL:3	n.262_265delGAAA		non_coding_transcript_exon	Exon 4 of 6

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111417 Hom.: 0 Cov.: 22

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: 4 AN: 1076901 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 344727

African (AFR) AF: 0.00 AC: 0 AN: 26003

American (AMR) AF: 0.00 AC: 0 AN: 35123

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19256

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30104

South Asian (SAS) AF: 0.00 AC: 0 AN: 53442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39565

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3728

European-Non Finnish (NFE) AF: 0.00000364 AC: 3 AN: 824306

Other (OTH) AF: 0.00 AC: 0 AN: 45374

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 111417 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33587

African (AFR) AF: 0.0000653 AC: 2 AN: 30632

American (AMR) AF: 0.00 AC: 0 AN: 10326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3584

South Asian (SAS) AF: 0.00 AC: 0 AN: 2676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6019

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53115

Other (OTH) AF: 0.00 AC: 0 AN: 1498

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Syndromic X-linked intellectual disability 14 (5)
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)
-	-	-	UPF3B-associated intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs794727881; hg19: chrX-118975168;