chrX-119851748-C-CTTTT

Variant names:

• chrX-119851748-C-CTTTT
• rs55712755
• NM_080632.3:c.263+15_263+18dupAAAA

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+15_263+18dupAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (137 hom., 326 hem., cov: 0)
  • Exomes 𝑓: 0.0016 (7 hom. 25 hem.)
  • Failed GnomAD Quality Control
• Consequence: UPF3B NM_080632.3 intron
• Clinical Significance: 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-CTTTT is Benign according to our data. Variant chrX-119851748-C-CTTTT is described in ClinVar as [Benign]. Clinvar id is 1590336.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+15_263+18dupAAAA		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+19insAAAA		intron_variant	Intron 2 of 10	1	NM_080632.3	ENSP00000276201.3
UPF3B	ENST00000345865.6	c.263+18_263+19insAAAA		intron_variant	Intron 2 of 9	1		ENSP00000245418.2

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 1539 AN: 64239 Hom.: 137 Cov.: 0

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00102

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0123

Gnomad NFE AF: 0.000226

Gnomad OTH AF: 0.0193

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00155 AC: 767 AN: 494684 Hom.: 7 Cov.: 0 AF XY: 0.000172 AC XY: 25 AN XY: 145192

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

African (AFR) AF: 0.0696 AC: 489 AN: 7030

American (AMR) AF: 0.00437 AC: 53 AN: 12141

Ashkenazi Jewish (ASJ) AF: 0.0000877 AC: 1 AN: 11404

East Asian (EAS) AF: 0.00174 AC: 26 AN: 14960

South Asian (SAS) AF: 0.000383 AC: 11 AN: 28729

European-Finnish (FIN) AF: 0.000114 AC: 3 AN: 26355

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1574

European-Non Finnish (NFE) AF: 0.000200 AC: 74 AN: 370190

Other (OTH) AF: 0.00493 AC: 110 AN: 22301

⚠️ 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: 0.0240 AC: 1539 AN: 64231 Hom.: 137 Cov.: 0 AF XY: 0.0286 AC XY: 326 AN XY: 11399

African (AFR) AF: 0.112 AC: 1426 AN: 12741

American (AMR) AF: 0.0197 AC: 87 AN: 4411

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

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

South Asian (SAS) AF: 0.00104 AC: 1 AN: 965

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

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

European-Non Finnish (NFE) AF: 0.000226 AC: 9 AN: 39750

Other (OTH) AF: 0.0190 AC: 15 AN: 788

Alfa AF: 0.00 Hom.: 585

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic X-linked intellectual disability 14 Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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;