X-119835112-A-C

Variant names:

• chrX-119835112-A-C
• rs2239963
• NM_080632.3:c.1303-85T>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_080632.3(UPF3B):​c.1303-85T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,103,928 control chromosomes in the GnomAD database, including 49,668 homozygotes. There are 118,354 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (3911 hom., 9663 hem., cov: 24)
  • Exomes 𝑓: 0.36 (45757 hom. 108691 hem.)
• Consequence: UPF3B NM_080632.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0310

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-119835112-A-C is Benign according to our data. Variant chrX-119835112-A-C is described in ClinVar as [Benign]. Clinvar id is 670829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF3B	NM_080632.3	c.1303-85T>G		intron_variant	Intron 10 of 10	ENST00000276201.7	NP_542199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPF3B	ENST00000276201.7	c.1303-85T>G		intron_variant	Intron 10 of 10	1	NM_080632.3	ENSP00000276201.3
UPF3B	ENST00000345865.6	c.1264-85T>G		intron_variant	Intron 9 of 9	1		ENSP00000245418.2

Frequencies

GnomAD3 genomes AF: 0.285 AC: 31813 AN: 111575 Hom.: 3913 Cov.: 24 AF XY: 0.286 AC XY: 9666 AN XY: 33775

Gnomad AFR AF: 0.0730

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.315

GnomAD4 exome AF: 0.361 AC: 357881 AN: 992299 Hom.: 45757 AF XY: 0.376 AC XY: 108691 AN XY: 289443

Gnomad4 AFR exome AF: 0.0700

Gnomad4 AMR exome AF: 0.548

Gnomad4 ASJ exome AF: 0.342

Gnomad4 EAS exome AF: 0.433

Gnomad4 SAS exome AF: 0.324

Gnomad4 FIN exome AF: 0.395

Gnomad4 NFE exome AF: 0.361

Gnomad4 OTH exome AF: 0.354

GnomAD4 genome AF: 0.285 AC: 31804 AN: 111629 Hom.: 3911 Cov.: 24 AF XY: 0.286 AC XY: 9663 AN XY: 33839

Gnomad4 AFR AF: 0.0728

Gnomad4 AMR AF: 0.444

Gnomad4 ASJ AF: 0.348

Gnomad4 EAS AF: 0.438

Gnomad4 SAS AF: 0.327

Gnomad4 FIN AF: 0.403

Gnomad4 NFE AF: 0.347

Gnomad4 OTH AF: 0.312

Alfa AF: 0.342 Hom.: 20412

Bravo AF: 0.290

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.2
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2239963; hg19: chrX-118969075;