X-119851748-CTTTTTTT-CTTTTTTTTTTTTTTTTTTTTT

Variant names:

• chrX-119851748-C-CTTTTTTTTTTTTTT
• rs55712755
• NM_080632.3:c.263+5_263+18dupAAAAAAAAAAAAAA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_080632.3(UPF3B):​c.263+5_263+18dupAAAAAAAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (244 hom., 300 hem., cov: 0)
  • Exomes 𝑓: 0.020 (85 hom. 792 hem.)
  • Failed GnomAD Quality Control
• Consequence: UPF3B NM_080632.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 -16 ACMG points.

• BP6: Variant X-119851748-C-CTTTTTTTTTTTTTT is Benign according to our data. Variant chrX-119851748-C-CTTTTTTTTTTTTTT is described in ClinVar as [Likely_benign]. Clinvar id is 1622841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0382 (2435/63815) while in subpopulation EAS AF = 0.0475 (68/1431). AF 95% confidence interval is 0.0397. There are 244 homozygotes in GnomAd4. There are 300 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 244 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF3B	NM_080632.3	c.263+5_263+18dupAAAAAAAAAAAAAA		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+19insAAAAAAAAAAAAAA		intron_variant	Intron 2 of 10	1	NM_080632.3	ENSP00000276201.3
UPF3B	ENST00000345865.6	c.263+18_263+19insAAAAAAAAAAAAAA		intron_variant	Intron 2 of 9	1		ENSP00000245418.2

Frequencies

GnomAD3 genomes AF: 0.0381 AC: 2434 AN: 63823 Hom.: 244 Cov.: 0

Gnomad AFR AF: 0.0300

Gnomad AMI AF: 0.0244

Gnomad AMR AF: 0.0382

Gnomad ASJ AF: 0.0407

Gnomad EAS AF: 0.0474

Gnomad SAS AF: 0.0395

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.0123

Gnomad NFE AF: 0.0413

Gnomad OTH AF: 0.0399

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0203 AC: 9703 AN: 478330 Hom.: 85 Cov.: 0 AF XY: 0.00577 AC XY: 792 AN XY: 137314

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

African (AFR) AF: 0.0334 AC: 241 AN: 7223

American (AMR) AF: 0.0549 AC: 628 AN: 11431

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 228 AN: 10982

East Asian (EAS) AF: 0.0543 AC: 765 AN: 14083

South Asian (SAS) AF: 0.0313 AC: 829 AN: 26468

European-Finnish (FIN) AF: 0.0157 AC: 399 AN: 25400

Middle Eastern (MID) AF: 0.0202 AC: 31 AN: 1535

European-Non Finnish (NFE) AF: 0.0171 AC: 6138 AN: 359716

Other (OTH) AF: 0.0207 AC: 444 AN: 21492

⚠️ 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: 0.0382 AC: 2435 AN: 63815 Hom.: 244 Cov.: 0 AF XY: 0.0264 AC XY: 300 AN XY: 11377

African (AFR) AF: 0.0300 AC: 381 AN: 12684

American (AMR) AF: 0.0382 AC: 168 AN: 4397

Ashkenazi Jewish (ASJ) AF: 0.0407 AC: 81 AN: 1992

East Asian (EAS) AF: 0.0475 AC: 68 AN: 1431

South Asian (SAS) AF: 0.0400 AC: 38 AN: 951

European-Finnish (FIN) AF: 0.0153 AC: 23 AN: 1508

Middle Eastern (MID) AF: 0.0133 AC: 1 AN: 75

European-Non Finnish (NFE) AF: 0.0413 AC: 1631 AN: 39459

Other (OTH) AF: 0.0395 AC: 31 AN: 785

Alfa AF: 0.0263 Hom.: 585

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Syndromic X-linked intellectual disability 14 Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 24, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jun 08, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

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

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;