X-119851748-CTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTT

Variant names:

• chrX-119851748-C-CTTTTTTTTTTTTTTTT
• rs55712755
• NM_080632.3:c.263+3_263+18dupAAAAAAAAAAAAAAAA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_080632.3(UPF3B):​c.263+3_263+18dupAAAAAAAAAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (32 hom., 23 hem., cov: 0)
  • Exomes 𝑓: 0.0025 (13 hom. 145 hem.)
  • Failed GnomAD Quality Control
• Consequence: UPF3B NM_080632.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 -16 ACMG points.

• BP6: Variant X-119851748-C-CTTTTTTTTTTTTTTTT is Benign according to our data. Variant chrX-119851748-C-CTTTTTTTTTTTTTTTT is described in ClinVar as Likely_benign. ClinVar VariationId is 589063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00311 (200/64206) while in subpopulation AFR AF = 0.0142 (181/12718). AF 95% confidence interval is 0.0125. There are 32 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 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+3_263+18dupAAAAAAAAAAAAAAAA		intron	N/A	NP_542199.1	Q9BZI7-1
	UPF3B	NM_023010.4		c.263+3_263+18dupAAAAAAAAAAAAAAAA		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+19insAAAAAAAAAAAAAAAA		intron	N/A	ENSP00000276201.3	Q9BZI7-1
	UPF3B	ENST00000345865.6	TSL:1	c.263+18_263+19insAAAAAAAAAAAAAAAA		intron	N/A	ENSP00000245418.2	Q9BZI7-2
	UPF3B	ENST00000951330.1		c.263+18_263+19insAAAAAAAAAAAAAAAA		intron	N/A	ENSP00000621389.1

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 200 AN: 64214 Hom.: 32 Cov.: 0

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000454

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000352

Gnomad OTH AF: 0.00386

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00252 AC: 1245 AN: 493603 Hom.: 13 Cov.: 0 AF XY: 0.00100 AC XY: 145 AN XY: 144721

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

African (AFR) AF: 0.0172 AC: 127 AN: 7396

American (AMR) AF: 0.00788 AC: 95 AN: 12061

Ashkenazi Jewish (ASJ) AF: 0.00237 AC: 27 AN: 11386

East Asian (EAS) AF: 0.00582 AC: 87 AN: 14939

South Asian (SAS) AF: 0.00661 AC: 187 AN: 28294

European-Finnish (FIN) AF: 0.00148 AC: 39 AN: 26274

Middle Eastern (MID) AF: 0.00253 AC: 4 AN: 1583

European-Non Finnish (NFE) AF: 0.00165 AC: 611 AN: 369363

Other (OTH) AF: 0.00305 AC: 68 AN: 22307

⚠️ 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: 0.00311 AC: 200 AN: 64206 Hom.: 32 Cov.: 0 AF XY: 0.00202 AC XY: 23 AN XY: 11400

African (AFR) AF: 0.0142 AC: 181 AN: 12718

American (AMR) AF: 0.000453 AC: 2 AN: 4412

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 1437

South Asian (SAS) AF: 0.00 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: 39749

Other (OTH) AF: 0.00382 AC: 3 AN: 786

Alfa AF: 0.00 Hom.: 585

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	Syndromic X-linked intellectual disability 14 (1)

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;