chrX-119851748-C-CTTTTTTTTTTTTT

Variant names:

• chrX-119851748-C-CTTTTTTTTTTTTT
• rs55712755
• NM_080632.3:c.263+6_263+18dupAAAAAAAAAAAAA

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+6_263+18dupAAAAAAAAAAAAA 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 0.35 (4282 hom., 2747 hem., cov: 0)
  • Exomes 𝑓: 0.041 (272 hom. 1917 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-CTTTTTTTTTTTTT is Benign according to our data. Variant chrX-119851748-C-CTTTTTTTTTTTTT is described in ClinVar as [Likely_benign]. Clinvar id is 1636570.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.59 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.346 AC: 21654 AN: 62495 Hom.: 4282 Cov.: 0

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.0938

Gnomad MID AF: 0.211

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.328

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0413 AC: 19018 AN: 460904 Hom.: 272 Cov.: 0 AF XY: 0.0146 AC XY: 1917 AN XY: 131546

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

African (AFR) AF: 0.0663 AC: 460 AN: 6936

American (AMR) AF: 0.0980 AC: 1059 AN: 10810

Ashkenazi Jewish (ASJ) AF: 0.0416 AC: 435 AN: 10446

East Asian (EAS) AF: 0.125 AC: 1650 AN: 13178

South Asian (SAS) AF: 0.0523 AC: 1342 AN: 25652

European-Finnish (FIN) AF: 0.0339 AC: 821 AN: 24241

Middle Eastern (MID) AF: 0.0363 AC: 52 AN: 1433

European-Non Finnish (NFE) AF: 0.0351 AC: 12217 AN: 347731

Other (OTH) AF: 0.0480 AC: 982 AN: 20477

⚠️ 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: 0.346 AC: 21651 AN: 62487 Hom.: 4282 Cov.: 0 AF XY: 0.243 AC XY: 2747 AN XY: 11327

African (AFR) AF: 0.321 AC: 4027 AN: 12530

American (AMR) AF: 0.428 AC: 1811 AN: 4228

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 766 AN: 1951

East Asian (EAS) AF: 0.624 AC: 878 AN: 1406

South Asian (SAS) AF: 0.261 AC: 243 AN: 931

European-Finnish (FIN) AF: 0.0938 AC: 136 AN: 1450

Middle Eastern (MID) AF: 0.185 AC: 12 AN: 65

European-Non Finnish (NFE) AF: 0.346 AC: 13386 AN: 38650

Other (OTH) AF: 0.328 AC: 250 AN: 762

Alfa AF: 0.0923 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 (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;