NM_080632.3:c.263+15_263+18delAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_080632.3(UPF3B):​c.263+15_263+18delAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 555,715 control chromosomes in the GnomAD database, including 2 homozygotes. There are 4 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 2 hem., cov: 0)
  • Exomes 𝑓: 0.0011 (2 hom. 2 hem.)
• Consequence: UPF3B NM_080632.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0510
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000125 (8/64214) while in subpopulation SAS AF = 0.00415 (4/965). AF 95% confidence interval is 0.00142. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF3B	NM_080632.3	c.263+15_263+18delAAAA		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+15_263+18delAAAA		intron_variant	Intron 2 of 10	1	NM_080632.3	ENSP00000276201.3
UPF3B	ENST00000345865.6	c.263+15_263+18delAAAA		intron_variant	Intron 2 of 9	1		ENSP00000245418.2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 8 AN: 64222 Hom.: 0 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: 0.00410

Gnomad FIN AF: 0.000656

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000252

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00114 AC: 558 AN: 491501 Hom.: 2 AF XY: 0.0000139 AC XY: 2 AN XY: 143619

⚠️ 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: 7478

American (AMR) AF: 0.000660 AC: 8 AN: 12127

Ashkenazi Jewish (ASJ) AF: 0.000799 AC: 9 AN: 11270

East Asian (EAS) AF: 0.000199 AC: 3 AN: 15052

South Asian (SAS) AF: 0.00112 AC: 32 AN: 28539

European-Finnish (FIN) AF: 0.000881 AC: 23 AN: 26092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1573

European-Non Finnish (NFE) AF: 0.00125 AC: 459 AN: 367106

Other (OTH) AF: 0.000988 AC: 22 AN: 22264

⚠️ 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 AF: 0.000125 AC: 8 AN: 64214 Hom.: 0 Cov.: 0 AF XY: 0.000175 AC XY: 2 AN XY: 11400

African (AFR) AF: 0.000157 AC: 2 AN: 12724

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: 0.00415 AC: 4 AN: 965

European-Finnish (FIN) AF: 0.000656 AC: 1 AN: 1524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 75

European-Non Finnish (NFE) AF: 0.0000252 AC: 1 AN: 39749

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

Alfa AF: 0.00 Hom.: 585

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.051

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55712755; hg19: chrX-118985711;