X-119851748-CTTTTT-CTTTTTTTTTTTTTTTTTTT

Position:

• chrX-119851748-CTTTTT-CTTTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_080632.3(UPF3B):​c.263+18_263+19insAAAAAAAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (244 hom., 300 hem., cov: 0)
  • Exomes 𝑓: 0.020 (85 hom. 792 hem.)
  • Failed GnomAD Quality Control
• Consequence: UPF3B NM_080632.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0650

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant X-119851748-C-CTTTTTTTTTTTTTT is Benign according to our data. Variant chrX-119851748-C-CTTTTTTTTTTTTTT is described in ClinVar as [Likely_benign]. Clinvar id is 1622841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0382 (2435/63815) while in subpopulation EAS AF= 0.0475 (68/1431). AF 95% confidence interval is 0.0397. There are 244 homozygotes in gnomad4. There are 300 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 244 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UPF3B	NM_080632.3	c.263+18_263+19insAAAAAAAAAAAAAA		intron_variant		ENST00000276201.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UPF3B	ENST00000276201.7	c.263+18_263+19insAAAAAAAAAAAAAA		intron_variant		1	NM_080632.3	A1
UPF3B	ENST00000345865.6	c.263+18_263+19insAAAAAAAAAAAAAA		intron_variant		1		P4

Frequencies

GnomAD3 genomes AF: 0.0381 AC: 2434 AN: 63823 Hom.: 244 Cov.: 0 AF XY: 0.0264 AC XY: 300 AN XY: 11379

Gnomad AFR AF: 0.0300

Gnomad AMI AF: 0.0244

Gnomad AMR AF: 0.0382

Gnomad ASJ AF: 0.0407

Gnomad EAS AF: 0.0474

Gnomad SAS AF: 0.0395

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.0123

Gnomad NFE AF: 0.0413

Gnomad OTH AF: 0.0399

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0203 AC: 9703 AN: 478330 Hom.: 85 Cov.: 0 AF XY: 0.00577 AC XY: 792 AN XY: 137314

Gnomad4 AFR exome AF: 0.0334

Gnomad4 AMR exome AF: 0.0549

Gnomad4 ASJ exome AF: 0.0208

Gnomad4 EAS exome AF: 0.0543

Gnomad4 SAS exome AF: 0.0313

Gnomad4 FIN exome AF: 0.0157

Gnomad4 NFE exome AF: 0.0171

Gnomad4 OTH exome AF: 0.0207

GnomAD4 genome AF: 0.0382 AC: 2435 AN: 63815 Hom.: 244 Cov.: 0 AF XY: 0.0264 AC XY: 300 AN XY: 11377

Gnomad4 AFR AF: 0.0300

Gnomad4 AMR AF: 0.0382

Gnomad4 ASJ AF: 0.0407

Gnomad4 EAS AF: 0.0475

Gnomad4 SAS AF: 0.0400

Gnomad4 FIN AF: 0.0153

Gnomad4 NFE AF: 0.0413

Gnomad4 OTH AF: 0.0395

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Syndromic X-linked intellectual disability 14 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 24, 2022	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs55712755; hg19: chrX-118985711;