X-119851748-CTTTTTTT-CTTTTTTTTTTTT

Variant names:

• chrX-119851748-C-CTTTTT
• rs55712755
• NM_080632.3:c.263+14_263+18dupAAAAA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_080632.3(UPF3B):​c.263+14_263+18dupAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.013 (52 hom., 176 hem., cov: 0)
  • Exomes 𝑓: 0.0016 (9 hom. 23 hem.)
  • Failed GnomAD Quality Control
• Consequence: UPF3B NM_080632.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 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: 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant X-119851748-C-CTTTTT is Benign according to our data. Variant chrX-119851748-C-CTTTTT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2039555.

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+14_263+18dupAAAAA		intron	N/A	NP_542199.1	Q9BZI7-1
	UPF3B	NM_023010.4		c.263+14_263+18dupAAAAA		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+19insAAAAA		intron	N/A	ENSP00000276201.3	Q9BZI7-1
	UPF3B	ENST00000345865.6	TSL:1	c.263+18_263+19insAAAAA		intron	N/A	ENSP00000245418.2	Q9BZI7-2
	UPF3B	ENST00000951330.1		c.263+18_263+19insAAAAA		intron	N/A	ENSP00000621389.1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 813 AN: 64215 Hom.: 52 Cov.: 0

Gnomad AFR AF: 0.0608

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00454

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000694

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000352

Gnomad OTH AF: 0.00642

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00157 AC: 777 AN: 493981 Hom.: 9 Cov.: 0 AF XY: 0.000159 AC XY: 23 AN XY: 144775

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

African (AFR) AF: 0.0476 AC: 338 AN: 7102

American (AMR) AF: 0.00281 AC: 34 AN: 12120

Ashkenazi Jewish (ASJ) AF: 0.000439 AC: 5 AN: 11396

East Asian (EAS) AF: 0.00527 AC: 78 AN: 14787

South Asian (SAS) AF: 0.000839 AC: 24 AN: 28608

European-Finnish (FIN) AF: 0.000190 AC: 5 AN: 26331

Middle Eastern (MID) AF: 0.00192 AC: 3 AN: 1566

European-Non Finnish (NFE) AF: 0.000592 AC: 219 AN: 369798

Other (OTH) AF: 0.00319 AC: 71 AN: 22273

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0127 AC: 814 AN: 64207 Hom.: 52 Cov.: 0 AF XY: 0.0154 AC XY: 176 AN XY: 11401

African (AFR) AF: 0.0609 AC: 774 AN: 12716

American (AMR) AF: 0.00453 AC: 20 AN: 4412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2002

East Asian (EAS) AF: 0.000696 AC: 1 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: 0.000352 AC: 14 AN: 39750

Other (OTH) AF: 0.00635 AC: 5 AN: 788

Alfa AF: 0.00 Hom.: 585

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Syndromic X-linked intellectual disability 14 (2)

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;