X-119851748-CTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant names:

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

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+19insAAAAAAAAAAAAAAAAAAAAAAAAAAAA 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 0.000093 (0 hom., 1 hem., cov: 0)
  • Exomes 𝑓: 0.000042 (0 hom. 1 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-CTTTTTTTTTTTTTTTTTTTTTTTTTTTT is Benign according to our data. Variant chrX-119851748-C-CTTTTTTTTTTTTTTTTTTTTTTTTTTTT is described in ClinVar as [Likely_benign]. Clinvar id is 2029467.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+19insAAAAAAAAAAAAAAAAAAAAAAAAAAAA		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+19insAAAAAAAAAAAAAAAAAAAAAAAAAAAA		intron_variant	Intron 2 of 10	1	NM_080632.3	ENSP00000276201.3
UPF3B	ENST00000345865.6	c.263+18_263+19insAAAAAAAAAAAAAAAAAAAAAAAAAAAA		intron_variant	Intron 2 of 9	1		ENSP00000245418.2

Frequencies

GnomAD3 genomes AF: 0.0000934 AC: 6 AN: 64223 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000227

Gnomad ASJ AF: 0.000500

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000252

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000423 AC: 21 AN: 495908 Hom.: 0 Cov.: 0 AF XY: 0.00000684 AC XY: 1 AN XY: 146096

African (AFR) AF: 0.00120 AC: 9 AN: 7491

American (AMR) AF: 0.000246 AC: 3 AN: 12190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11429

East Asian (EAS) AF: 0.000199 AC: 3 AN: 15069

South Asian (SAS) AF: 0.0000694 AC: 2 AN: 28811

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1586

European-Non Finnish (NFE) AF: 0.00000270 AC: 1 AN: 370544

Other (OTH) AF: 0.000134 AC: 3 AN: 22424

GnomAD4 genome AF: 0.0000934 AC: 6 AN: 64215 Hom.: 0 Cov.: 0 AF XY: 0.0000877 AC XY: 1 AN XY: 11401

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

African (AFR) AF: 0.000236 AC: 3 AN: 12724

American (AMR) AF: 0.000227 AC: 1 AN: 4412

Ashkenazi Jewish (ASJ) AF: 0.000500 AC: 1 AN: 2002

East Asian (EAS) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 75

European-Non Finnish (NFE) AF: 0.0000252 AC: 1 AN: 39750

Other (OTH) AF: 0.00 AC: 0 AN: 788

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000039), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic X-linked intellectual disability 14 Benign:1

Mar 13, 2024

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

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;