X-119851748-CTTTTTTT-CTTTTTTTTTTTTTT

Variant names:

• chrX-119851748-C-CTTTTTTT
• rs55712755
• NM_080632.3:c.263+12_263+18dupAAAAAAA

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+12_263+18dupAAAAAAA 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 0.0036 (16 hom., 42 hem., cov: 0)
  • Exomes 𝑓: 0.0045 (16 hom. 96 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-CTTTTTTT is Benign according to our data. Variant chrX-119851748-C-CTTTTTTT is described in ClinVar as [Likely_benign]. Clinvar id is 1636009.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00363 (233/64209) while in subpopulation AFR AF = 0.0109 (139/12718). AF 95% confidence interval is 0.00945. There are 16 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF3B	NM_080632.3	c.263+12_263+18dupAAAAAAA		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+19insAAAAAAA		intron_variant	Intron 2 of 10	1	NM_080632.3	ENSP00000276201.3
UPF3B	ENST00000345865.6	c.263+18_263+19insAAAAAAA		intron_variant	Intron 2 of 9	1		ENSP00000245418.2

Frequencies

GnomAD3 genomes AF: 0.00361 AC: 232 AN: 64217 Hom.: 16 Cov.: 0

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00521

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00205

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00164

Gnomad OTH AF: 0.00513

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00453 AC: 2221 AN: 490120 Hom.: 16 Cov.: 0 AF XY: 0.000672 AC XY: 96 AN XY: 142914

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

African (AFR) AF: 0.0149 AC: 108 AN: 7271

American (AMR) AF: 0.00757 AC: 91 AN: 12015

Ashkenazi Jewish (ASJ) AF: 0.00452 AC: 51 AN: 11282

East Asian (EAS) AF: 0.0307 AC: 437 AN: 14212

South Asian (SAS) AF: 0.00588 AC: 165 AN: 28070

European-Finnish (FIN) AF: 0.00240 AC: 63 AN: 26222

Middle Eastern (MID) AF: 0.0116 AC: 18 AN: 1546

European-Non Finnish (NFE) AF: 0.00309 AC: 1137 AN: 367425

Other (OTH) AF: 0.00684 AC: 151 AN: 22077

⚠️ 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: 0.00363 AC: 233 AN: 64209 Hom.: 16 Cov.: 0 AF XY: 0.00368 AC XY: 42 AN XY: 11401

African (AFR) AF: 0.0109 AC: 139 AN: 12718

American (AMR) AF: 0.00521 AC: 23 AN: 4414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2002

East Asian (EAS) AF: 0.00 AC: 0 AN: 1437

South Asian (SAS) AF: 0.00207 AC: 2 AN: 965

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 75

European-Non Finnish (NFE) AF: 0.00164 AC: 65 AN: 39748

Other (OTH) AF: 0.00508 AC: 4 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 23, 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;