X-119851748-CTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_080632.3(UPF3B):​c.263+18_263+19insAAAAAAAAAAAAAAAAAAAAAAAAAAAAA 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 0.000062 (1 hom., 0 hem., cov: 0)
  • Exomes 𝑓: 0.000018 (0 hom. 2 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000623 (4/64215) while in subpopulation AFR AF = 0.000314 (4/12722). AF 95% confidence interval is 0.000107. There are 1 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0000623 AC: 4 AN: 64223 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000315

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: 0.0000181 AC: 9 AN: 495909 Hom.: 0 Cov.: 0 AF XY: 0.0000137 AC XY: 2 AN XY: 146097

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

African (AFR) AF: 0.000667 AC: 5 AN: 7491

American (AMR) AF: 0.00 AC: 0 AN: 12189

Ashkenazi Jewish (ASJ) AF: 0.0000875 AC: 1 AN: 11429

East Asian (EAS) AF: 0.00 AC: 0 AN: 15067

South Asian (SAS) AF: 0.0000694 AC: 2 AN: 28812

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: 370546

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000029), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000623 AC: 4 AN: 64215 Hom.: 1 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 11401

African (AFR) AF: 0.000314 AC: 4 AN: 12722

American (AMR) AF: 0.00 AC: 0 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: 0.00 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: 0.00 AC: 0 AN: 39750

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

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;