X-119851748-CTTTTTTT-CTTTT

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_080632.3(UPF3B):​c.263+16_263+18delAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0073 in 539,081 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000016 (0 hom., 0 hem., cov: 0)
  • Exomes 𝑓: 0.0083 (0 hom. 0 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: Uncertain_significance. The variant received 0 ACMG points.

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+18delAAA		intron	N/A	NP_542199.1	Q9BZI7-1
	UPF3B	NM_023010.4		c.263+16_263+18delAAA		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+16_263+18delAAA		intron	N/A	ENSP00000276201.3	Q9BZI7-1
	UPF3B	ENST00000345865.6	TSL:1	c.263+16_263+18delAAA		intron	N/A	ENSP00000245418.2	Q9BZI7-2
	UPF3B	ENST00000951330.1		c.263+16_263+18delAAA		intron	N/A	ENSP00000621389.1

Frequencies

GnomAD3 genomes AF: 0.0000156 AC: 1 AN: 64212 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000252

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00828 AC: 3932 AN: 474869 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133751

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

African (AFR) AF: 0.00161 AC: 12 AN: 7443

American (AMR) AF: 0.00405 AC: 48 AN: 11865

Ashkenazi Jewish (ASJ) AF: 0.00971 AC: 105 AN: 10817

East Asian (EAS) AF: 0.00114 AC: 17 AN: 14967

South Asian (SAS) AF: 0.00376 AC: 103 AN: 27380

European-Finnish (FIN) AF: 0.00786 AC: 197 AN: 25079

Middle Eastern (MID) AF: 0.00461 AC: 7 AN: 1518

European-Non Finnish (NFE) AF: 0.00932 AC: 3303 AN: 354274

Other (OTH) AF: 0.00650 AC: 140 AN: 21526

⚠️ 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: 0.0000156 AC: 1 AN: 64212 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 11394

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

African (AFR) AF: 0.00 AC: 0 AN: 12718

American (AMR) AF: 0.00 AC: 0 AN: 4410

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 1441

South Asian (SAS) AF: 0.00 AC: 0 AN: 975

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 81

European-Non Finnish (NFE) AF: 0.0000252 AC: 1 AN: 39746

Other (OTH) AF: 0.00 AC: 0 AN: 779

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs55712755; hg19: chrX-118985711;