X-119851748-CTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_080632.3(UPF3B):​c.263+18_263+19insAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000031 (1 hom., 0 hem., cov: 0)
  • Exomes 𝑓: 0.000012 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: UPF3B NM_080632.3 intron
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0000311 AC: 2 AN: 64225 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000121 AC: 6 AN: 495912 Hom.: 0 Cov.: 0 AF XY: 0.00000684 AC XY: 1 AN XY: 146098

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

African (AFR) AF: 0.000267 AC: 2 AN: 7492

American (AMR) AF: 0.00 AC: 0 AN: 12191

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 15069

South Asian (SAS) AF: 0.0000347 AC: 1 AN: 28813

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: 0.00000810 AC: 3 AN: 370543

Other (OTH) AF: 0.00 AC: 0 AN: 22425

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.005362), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000311 AC: 2 AN: 64225 Hom.: 1 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 11403

African (AFR) AF: 0.000157 AC: 2 AN: 12718

American (AMR) AF: 0.00 AC: 0 AN: 4411

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 1441

South Asian (SAS) AF: 0.00 AC: 0 AN: 976

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 81

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 39755

Other (OTH) AF: 0.00 AC: 0 AN: 779

ClinVar

Not reported in ClinVar

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;