rs2428212

Variant names:

• chrX-119851635-C-T
• rs2428212
• NM_080632.3:c.264-34G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-119851635-C-T
• chrX-119851635-C-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_080632.3(UPF3B):​c.264-34G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (19401 hom., 21195 hem., cov: 21)
  • Exomes 𝑓: 0.58 (118123 hom. 169250 hem.)
  • Failed GnomAD Quality Control
• Consequence: UPF3B NM_080632.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.545
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-119851635-C-T is Benign according to our data. Variant chrX-119851635-C-T is described in ClinVar as Benign. ClinVar VariationId is 670475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.264-34G>A		intron	N/A	NP_542199.1	Q9BZI7-1
	UPF3B	NM_023010.4		c.264-34G>A		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.264-34G>A		intron	N/A	ENSP00000276201.3	Q9BZI7-1
	UPF3B	ENST00000345865.6	TSL:1	c.264-34G>A		intron	N/A	ENSP00000245418.2	Q9BZI7-2
	UPF3B	ENST00000951330.1		c.264-34G>A		intron	N/A	ENSP00000621389.1

Frequencies

GnomAD3 genomes AF: 0.680 AC: 74260 AN: 109182 Hom.: 19407 Cov.: 21

Gnomad AFR AF: 0.925

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.762

Gnomad ASJ AF: 0.587

Gnomad EAS AF: 0.945

Gnomad SAS AF: 0.673

Gnomad FIN AF: 0.503

Gnomad MID AF: 0.710

Gnomad NFE AF: 0.533

Gnomad OTH AF: 0.682

GnomAD2 exomes AF: 0.658 AC: 114572 AN: 174209 AF XY: 0.643

Gnomad AFR exome AF: 0.938

Gnomad AMR exome AF: 0.826

Gnomad ASJ exome AF: 0.574

Gnomad EAS exome AF: 0.942

Gnomad FIN exome AF: 0.512

Gnomad NFE exome AF: 0.535

Gnomad OTH exome AF: 0.631

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.583 AC: 562653 AN: 964815 Hom.: 118123 Cov.: 18 AF XY: 0.601 AC XY: 169250 AN XY: 281509

African (AFR) AF: 0.939 AC: 22408 AN: 23856

American (AMR) AF: 0.824 AC: 28661 AN: 34780

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 10540 AN: 18495

East Asian (EAS) AF: 0.950 AC: 28147 AN: 29630

South Asian (SAS) AF: 0.670 AC: 34136 AN: 50920

European-Finnish (FIN) AF: 0.508 AC: 20446 AN: 40246

Middle Eastern (MID) AF: 0.655 AC: 2527 AN: 3860

European-Non Finnish (NFE) AF: 0.541 AC: 390001 AN: 721421

Other (OTH) AF: 0.620 AC: 25787 AN: 41607

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.680 AC: 74301 AN: 109224 Hom.: 19401 Cov.: 21 AF XY: 0.672 AC XY: 21195 AN XY: 31546

African (AFR) AF: 0.926 AC: 27765 AN: 29999

American (AMR) AF: 0.762 AC: 7726 AN: 10133

Ashkenazi Jewish (ASJ) AF: 0.587 AC: 1537 AN: 2618

East Asian (EAS) AF: 0.945 AC: 3321 AN: 3513

South Asian (SAS) AF: 0.672 AC: 1723 AN: 2563

European-Finnish (FIN) AF: 0.503 AC: 2763 AN: 5498

Middle Eastern (MID) AF: 0.697 AC: 147 AN: 211

European-Non Finnish (NFE) AF: 0.533 AC: 28001 AN: 52544

Other (OTH) AF: 0.679 AC: 1004 AN: 1478

Alfa AF: 0.624 Hom.: 9173

Bravo AF: 0.720

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Syndromic X-linked intellectual disability 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.4
DANN	Benign	0.58
PhyloP100		0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2428212; hg19: chrX-118985598;