X-119851748-CTTTTTTT-CTTTTTTTTT

Variant names:

• chrX-119851748-C-CTT
• rs55712755
• NM_080632.3:c.263+17_263+18dupAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_080632.3(UPF3B):​c.263+17_263+18dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (12 hom., 58 hem., cov: 0)
  • Exomes 𝑓: 0.0031 (15 hom. 47 hem.)
• Consequence: UPF3B NM_080632.3 intron
• Clinical Significance: 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: Benign. The variant received -10 ACMG points.

• BP6: Variant X-119851748-C-CTT is Benign according to our data. Variant chrX-119851748-C-CTT is described in ClinVar as [Benign]. Clinvar id is 1579699.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00466 (299/64213) while in subpopulation NFE AF = 0.00523 (208/39748). AF 95% confidence interval is 0.00465. There are 12 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF3B	NM_080632.3	c.263+17_263+18dupAA		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+19insAA		intron_variant	Intron 2 of 10	1	NM_080632.3	ENSP00000276201.3
UPF3B	ENST00000345865.6	c.263+18_263+19insAA		intron_variant	Intron 2 of 9	1		ENSP00000245418.2

Frequencies

GnomAD3 genomes AF: 0.00466 AC: 299 AN: 64221 Hom.: 12 Cov.: 0

Gnomad AFR AF: 0.00149

Gnomad AMI AF: 0.0506

Gnomad AMR AF: 0.000907

Gnomad ASJ AF: 0.00150

Gnomad EAS AF: 0.00139

Gnomad SAS AF: 0.00205

Gnomad FIN AF: 0.0170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00523

Gnomad OTH AF: 0.0103

GnomAD4 exome AF: 0.00312 AC: 1544 AN: 494169 Hom.: 15 Cov.: 0 AF XY: 0.000324 AC XY: 47 AN XY: 144969

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

African (AFR) AF: 0.00714 AC: 52 AN: 7288

American (AMR) AF: 0.00115 AC: 14 AN: 12163

Ashkenazi Jewish (ASJ) AF: 0.000350 AC: 4 AN: 11417

East Asian (EAS) AF: 0.000864 AC: 13 AN: 15050

South Asian (SAS) AF: 0.000313 AC: 9 AN: 28772

European-Finnish (FIN) AF: 0.00818 AC: 214 AN: 26153

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1584

European-Non Finnish (NFE) AF: 0.00316 AC: 1168 AN: 369410

Other (OTH) AF: 0.00313 AC: 70 AN: 22332

⚠️ 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: 0.00466 AC: 299 AN: 64213 Hom.: 12 Cov.: 0 AF XY: 0.00509 AC XY: 58 AN XY: 11399

African (AFR) AF: 0.00149 AC: 19 AN: 12724

American (AMR) AF: 0.000906 AC: 4 AN: 4414

Ashkenazi Jewish (ASJ) AF: 0.00150 AC: 3 AN: 2002

East Asian (EAS) AF: 0.00139 AC: 2 AN: 1437

South Asian (SAS) AF: 0.00207 AC: 2 AN: 965

European-Finnish (FIN) AF: 0.0170 AC: 26 AN: 1526

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

European-Non Finnish (NFE) AF: 0.00523 AC: 208 AN: 39748

Other (OTH) AF: 0.0102 AC: 8 AN: 788

Alfa AF: 0.00 Hom.: 585

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic X-linked intellectual disability 14 Benign:1

Oct 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

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;