X-119851748-CTTTTTTT-CTTTTTTTTTTTTTTT

Variant names:

• chrX-119851748-C-CTTTTTTTT
• rs55712755
• NM_080632.3:c.263+11_263+18dupAAAAAAAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_080632.3(UPF3B):​c.263+11_263+18dupAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.030 (127 hom., 334 hem., cov: 0)
  • Exomes 𝑓: 0.010 (102 hom. 383 hem.)
  • Failed GnomAD Quality Control
• Consequence: UPF3B NM_080632.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0650
• Publications: 0 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: Benign. The variant received -10 ACMG points.

• BP6: Variant X-119851748-C-CTTTTTTTT is Benign according to our data. Variant chrX-119851748-C-CTTTTTTTT is described in ClinVar as [Likely_benign]. Clinvar id is 1594434.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF3B	NM_080632.3	c.263+11_263+18dupAAAAAAAA		intron_variant	Intron 2 of 10	ENST00000276201.7	NP_542199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPF3B	ENST00000276201.7	c.263+18_263+19insAAAAAAAA		intron_variant	Intron 2 of 10	1	NM_080632.3	ENSP00000276201.3
UPF3B	ENST00000345865.6	c.263+18_263+19insAAAAAAAA		intron_variant	Intron 2 of 9	1		ENSP00000245418.2

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 1927 AN: 64116 Hom.: 127 Cov.: 0

Gnomad AFR AF: 0.0385

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.0506

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.0669

Gnomad FIN AF: 0.00524

Gnomad MID AF: 0.0370

Gnomad NFE AF: 0.0246

Gnomad OTH AF: 0.0398

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0102 AC: 4940 AN: 485605 Hom.: 102 Cov.: 0 AF XY: 0.00273 AC XY: 383 AN XY: 140405

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0219 AC: 159 AN: 7257

American (AMR) AF: 0.0162 AC: 192 AN: 11854

Ashkenazi Jewish (ASJ) AF: 0.0137 AC: 153 AN: 11163

East Asian (EAS) AF: 0.0565 AC: 775 AN: 13711

South Asian (SAS) AF: 0.0171 AC: 467 AN: 27310

European-Finnish (FIN) AF: 0.00634 AC: 165 AN: 26035

Middle Eastern (MID) AF: 0.0282 AC: 43 AN: 1524

European-Non Finnish (NFE) AF: 0.00733 AC: 2674 AN: 364916

Other (OTH) AF: 0.0143 AC: 312 AN: 21835

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0301 AC: 1927 AN: 64108 Hom.: 127 Cov.: 0 AF XY: 0.0293 AC XY: 334 AN XY: 11398

African (AFR) AF: 0.0385 AC: 489 AN: 12698

American (AMR) AF: 0.0188 AC: 83 AN: 4406

Ashkenazi Jewish (ASJ) AF: 0.0506 AC: 101 AN: 1996

East Asian (EAS) AF: 0.119 AC: 169 AN: 1425

South Asian (SAS) AF: 0.0666 AC: 64 AN: 961

European-Finnish (FIN) AF: 0.00524 AC: 8 AN: 1526

Middle Eastern (MID) AF: 0.0400 AC: 3 AN: 75

European-Non Finnish (NFE) AF: 0.0246 AC: 978 AN: 39697

Other (OTH) AF: 0.0406 AC: 32 AN: 788

Alfa AF: 0.00355 Hom.: 585

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic X-linked intellectual disability 14 Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.065
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55712755; hg19: chrX-118985711;