X-119851748-CTTTTTTT-CTTTTTTTTTT

Variant names:

• chrX-119851748-C-CTTT
• rs55712755
• NM_080632.3:c.263+16_263+18dupAAA

Variant summary

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

The NM_080632.3(UPF3B):​c.263+16_263+18dupAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00064 (1 hom., 8 hem., cov: 0)
  • Exomes 𝑓: 0.00075 (6 hom. 17 hem.)
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 afr. GnomAd4 allele frequency = 0.000638 (41/64217) while in subpopulation AFR AF = 0.00283 (36/12724). AF 95% confidence interval is 0.0021. There are 1 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 8 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080632.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UPF3B	NM_080632.3	MANE Select	c.263+16_263+18dupAAA		intron	N/A	NP_542199.1	Q9BZI7-1
	UPF3B	NM_023010.4		c.263+16_263+18dupAAA		intron	N/A	NP_075386.1	Q9BZI7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UPF3B	ENST00000276201.7	TSL:1 MANE Select	c.263+18_263+19insAAA		intron	N/A	ENSP00000276201.3	Q9BZI7-1
	UPF3B	ENST00000345865.6	TSL:1	c.263+18_263+19insAAA		intron	N/A	ENSP00000245418.2	Q9BZI7-2
	UPF3B	ENST00000951330.1		c.263+18_263+19insAAA		intron	N/A	ENSP00000621389.1

Frequencies

GnomAD3 genomes AF: 0.000638 AC: 41 AN: 64225 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00208

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000655

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00128

GnomAD4 exome AF: 0.000753 AC: 373 AN: 495092 Hom.: 6 Cov.: 0 AF XY: 0.000117 AC XY: 17 AN XY: 145536

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

African (AFR) AF: 0.0262 AC: 188 AN: 7185

American (AMR) AF: 0.00198 AC: 24 AN: 12146

Ashkenazi Jewish (ASJ) AF: 0.000350 AC: 4 AN: 11421

East Asian (EAS) AF: 0.000732 AC: 11 AN: 15019

South Asian (SAS) AF: 0.000486 AC: 14 AN: 28779

European-Finnish (FIN) AF: 0.000418 AC: 11 AN: 26333

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1576

European-Non Finnish (NFE) AF: 0.000243 AC: 90 AN: 370278

Other (OTH) AF: 0.00139 AC: 31 AN: 22355

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000638 AC: 41 AN: 64217 Hom.: 1 Cov.: 0 AF XY: 0.000702 AC XY: 8 AN XY: 11401

African (AFR) AF: 0.00283 AC: 36 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: 0.00209 AC: 3 AN: 1437

South Asian (SAS) AF: 0.00 AC: 0 AN: 965

European-Finnish (FIN) AF: 0.000655 AC: 1 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: 0.00127 AC: 1 AN: 788

Alfa AF: 0.00 Hom.: 585

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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;