NM_080632.3:c.263+4_263+18dupAAAAAAAAAAAAAAA

Variant names:

• chrX-119851748-C-CTTTTTTTTTTTTTTT
• rs55712755
• NM_080632.3:c.263+4_263+18dupAAAAAAAAAAAAAAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_080632.3(UPF3B):​c.263+4_263+18dupAAAAAAAAAAAAAAA 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 0.0066 (48 hom., 45 hem., cov: 0)
  • Exomes 𝑓: 0.0081 (29 hom. 351 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-CTTTTTTTTTTTTTTT is Benign according to our data. Variant chrX-119851748-C-CTTTTTTTTTTTTTTT is described in ClinVar as [Likely_benign]. Clinvar id is 1673848.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00659 (423/64163) while in subpopulation AFR AF = 0.0192 (244/12706). AF 95% confidence interval is 0.0172. There are 48 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 48 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF3B	NM_080632.3	c.263+4_263+18dupAAAAAAAAAAAAAAA		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+19insAAAAAAAAAAAAAAA		intron_variant	Intron 2 of 10	1	NM_080632.3	ENSP00000276201.3
UPF3B	ENST00000345865.6	c.263+18_263+19insAAAAAAAAAAAAAAA		intron_variant	Intron 2 of 9	1		ENSP00000245418.2

Frequencies

GnomAD3 genomes AF: 0.00658 AC: 422 AN: 64171 Hom.: 48 Cov.: 0

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.00373

Gnomad AMR AF: 0.00567

Gnomad ASJ AF: 0.000500

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.000655

Gnomad MID AF: 0.0123

Gnomad NFE AF: 0.00320

Gnomad OTH AF: 0.00642

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00815 AC: 3982 AN: 488773 Hom.: 29 Cov.: 0 AF XY: 0.00247 AC XY: 351 AN XY: 142091

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

African (AFR) AF: 0.0247 AC: 180 AN: 7289

American (AMR) AF: 0.0271 AC: 321 AN: 11826

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 81 AN: 11253

East Asian (EAS) AF: 0.0195 AC: 286 AN: 14640

South Asian (SAS) AF: 0.0163 AC: 450 AN: 27551

European-Finnish (FIN) AF: 0.00553 AC: 144 AN: 26038

Middle Eastern (MID) AF: 0.00834 AC: 13 AN: 1559

European-Non Finnish (NFE) AF: 0.00629 AC: 2304 AN: 366558

Other (OTH) AF: 0.00920 AC: 203 AN: 22059

⚠️ 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: 0.00659 AC: 423 AN: 64163 Hom.: 48 Cov.: 0 AF XY: 0.00395 AC XY: 45 AN XY: 11401

African (AFR) AF: 0.0192 AC: 244 AN: 12706

American (AMR) AF: 0.00567 AC: 25 AN: 4412

Ashkenazi Jewish (ASJ) AF: 0.000500 AC: 1 AN: 2002

East Asian (EAS) AF: 0.00348 AC: 5 AN: 1437

South Asian (SAS) AF: 0.0125 AC: 12 AN: 963

European-Finnish (FIN) AF: 0.000655 AC: 1 AN: 1526

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

European-Non Finnish (NFE) AF: 0.00320 AC: 127 AN: 39718

Other (OTH) AF: 0.00635 AC: 5 AN: 788

Alfa AF: 0.00 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

Feb 03, 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;