X-119851748-CTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTT

Variant names:

• chrX-119851748-C-CTTTTTTTTTTTTTTTTTT
• rs55712755
• NM_080632.3:c.263+18_263+19insAAAAAAAAAAAAAAAAAA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_080632.3(UPF3B):​c.263+18_263+19insAAAAAAAAAAAAAAAAAA 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 0.010 (107 hom., 63 hem., cov: 0)
  • Exomes 𝑓: 0.0010 (4 hom. 93 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant X-119851748-C-CTTTTTTTTTTTTTTTTTT is Benign according to our data. Variant chrX-119851748-C-CTTTTTTTTTTTTTTTTTT is described in ClinVar as [Likely_benign]. Clinvar id is 1555853.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 653 AN: 64184 Hom.: 107 Cov.: 0

Gnomad AFR AF: 0.0444

Gnomad AMI AF: 0.00373

Gnomad AMR AF: 0.00454

Gnomad ASJ AF: 0.000500

Gnomad EAS AF: 0.000695

Gnomad SAS AF: 0.00922

Gnomad FIN AF: 0.000655

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.0103

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00101 AC: 501 AN: 495271 Hom.: 4 Cov.: 0 AF XY: 0.000638 AC XY: 93 AN XY: 145739

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

African (AFR) AF: 0.0149 AC: 110 AN: 7384

American (AMR) AF: 0.00420 AC: 51 AN: 12156

Ashkenazi Jewish (ASJ) AF: 0.000876 AC: 10 AN: 11411

East Asian (EAS) AF: 0.00133 AC: 20 AN: 15036

South Asian (SAS) AF: 0.00429 AC: 123 AN: 28655

European-Finnish (FIN) AF: 0.000645 AC: 17 AN: 26352

Middle Eastern (MID) AF: 0.00127 AC: 2 AN: 1578

European-Non Finnish (NFE) AF: 0.000389 AC: 144 AN: 370310

Other (OTH) AF: 0.00107 AC: 24 AN: 22389

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0102 AC: 653 AN: 64176 Hom.: 107 Cov.: 0 AF XY: 0.00553 AC XY: 63 AN XY: 11400

African (AFR) AF: 0.0444 AC: 564 AN: 12697

American (AMR) AF: 0.00453 AC: 20 AN: 4412

Ashkenazi Jewish (ASJ) AF: 0.000500 AC: 1 AN: 2000

East Asian (EAS) AF: 0.000697 AC: 1 AN: 1435

South Asian (SAS) AF: 0.00933 AC: 9 AN: 965

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

Middle Eastern (MID) AF: 0.0137 AC: 1 AN: 73

European-Non Finnish (NFE) AF: 0.00116 AC: 46 AN: 39744

Other (OTH) AF: 0.0102 AC: 8 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

Jan 15, 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;