chrX-119851748-C-CTTTTTT

Variant names:

• chrX-119851748-C-CTTTTTT
• rs55712755
• NM_080632.3:c.263+13_263+18dupAAAAAA

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+13_263+18dupAAAAAA 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 0.013 (75 hom., 176 hem., cov: 0)
  • Exomes 𝑓: 0.0023 (12 hom. 42 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-CTTTTTT is Benign according to our data. Variant chrX-119851748-C-CTTTTTT is described in ClinVar as [Likely_benign]. Clinvar id is 1635780.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+13_263+18dupAAAAAA		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+19insAAAAAA		intron_variant	Intron 2 of 10	1	NM_080632.3	ENSP00000276201.3
UPF3B	ENST00000345865.6	c.263+18_263+19insAAAAAA		intron_variant	Intron 2 of 9	1		ENSP00000245418.2

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 846 AN: 64226 Hom.: 75 Cov.: 0

Gnomad AFR AF: 0.0625

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00634

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00139

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0123

Gnomad NFE AF: 0.000277

Gnomad OTH AF: 0.0116

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00226 AC: 1113 AN: 492481 Hom.: 12 Cov.: 0 AF XY: 0.000292 AC XY: 42 AN XY: 143905

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

African (AFR) AF: 0.0320 AC: 229 AN: 7166

American (AMR) AF: 0.00348 AC: 42 AN: 12070

Ashkenazi Jewish (ASJ) AF: 0.00238 AC: 27 AN: 11326

East Asian (EAS) AF: 0.0123 AC: 179 AN: 14533

South Asian (SAS) AF: 0.00180 AC: 51 AN: 28363

European-Finnish (FIN) AF: 0.000761 AC: 20 AN: 26287

Middle Eastern (MID) AF: 0.00704 AC: 11 AN: 1562

European-Non Finnish (NFE) AF: 0.00125 AC: 463 AN: 368961

Other (OTH) AF: 0.00410 AC: 91 AN: 22213

⚠️ 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: 0.0132 AC: 849 AN: 64218 Hom.: 75 Cov.: 0 AF XY: 0.0154 AC XY: 176 AN XY: 11400

African (AFR) AF: 0.0627 AC: 798 AN: 12721

American (AMR) AF: 0.00634 AC: 28 AN: 4418

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

East Asian (EAS) AF: 0.00139 AC: 2 AN: 1437

South Asian (SAS) AF: 0.00 AC: 0 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: 0.000277 AC: 11 AN: 39750

Other (OTH) AF: 0.0114 AC: 9 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 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;