chrX-119841119-C-T

Variant names:

• chrX-119841119-C-T
• rs142862074
• NM_080632.3:c.764G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_080632.3(UPF3B):​c.764G>A​(p.Arg255Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000378 in 1,205,647 control chromosomes in the GnomAD database, including 3 homozygotes. There are 107 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R255G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., 52 hem., cov: 23)
  • Exomes 𝑓: 0.00021 (1 hom. 55 hem.)
• Consequence: UPF3B NM_080632.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.08
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038240254).
• BP6: Variant X-119841119-C-T is Benign according to our data. Variant chrX-119841119-C-T is described in ClinVar as Benign. ClinVar VariationId is 536851.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 = 0.00199 (222/111608) while in subpopulation AFR AF = 0.00689 (212/30758). AF 95% confidence interval is 0.00613. There are 2 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.764G>A	p.Arg255Lys	missense	Exon 7 of 11	NP_542199.1	Q9BZI7-1
	UPF3B	NM_023010.4		c.764G>A	p.Arg255Lys	missense	Exon 7 of 10	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.764G>A	p.Arg255Lys	missense	Exon 7 of 11	ENSP00000276201.3	Q9BZI7-1
	UPF3B	ENST00000345865.6	TSL:1	c.764G>A	p.Arg255Lys	missense	Exon 7 of 10	ENSP00000245418.2	Q9BZI7-2
	UPF3B	ENST00000951330.1		c.881G>A	p.Arg294Lys	missense	Exon 8 of 11	ENSP00000621389.1

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 223 AN: 111554 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.00691

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000670

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: 0.0000188

Gnomad OTH AF: 0.00200

GnomAD2 exomes AF: 0.000575 AC: 103 AN: 179041 AF XY: 0.000246

Gnomad AFR exome AF: 0.00687

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000126

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.000214 AC: 234 AN: 1094039 Hom.: 1 Cov.: 30 AF XY: 0.000153 AC XY: 55 AN XY: 359629

African (AFR) AF: 0.00753 AC: 198 AN: 26309

American (AMR) AF: 0.000343 AC: 12 AN: 34995

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19343

East Asian (EAS) AF: 0.00 AC: 0 AN: 30149

South Asian (SAS) AF: 0.00 AC: 0 AN: 53490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40360

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4119

European-Non Finnish (NFE) AF: 0.00000357 AC: 3 AN: 839319

Other (OTH) AF: 0.000435 AC: 20 AN: 45955

GnomAD4 genome AF: 0.00199 AC: 222 AN: 111608 Hom.: 2 Cov.: 23 AF XY: 0.00154 AC XY: 52 AN XY: 33816

African (AFR) AF: 0.00689 AC: 212 AN: 30758

American (AMR) AF: 0.000573 AC: 6 AN: 10468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.00 AC: 0 AN: 2702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53073

Other (OTH) AF: 0.00197 AC: 3 AN: 1519

Alfa AF: 0.00127 Hom.: 28

Bravo AF: 0.00211

ESP6500AA AF: 0.00834 AC: 32

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000700 AC: 85

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	Syndromic X-linked intellectual disability 14 (1)
-	-	1	UPF3B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.016	T
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.1
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.15
Sift	Benign	0.63	T
Sift4G	Benign	0.85	T
Polyphen		0.064	B
Vest4		0.12
MVP		0.47
MPC		0.43
ClinPred		0.0056	T
GERP RS		4.6
Varity_R		0.20
gMVP		0.035
Mutation Taster		=92/8	polymorphism

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: rs142862074; hg19: chrX-118975082; COSMIC: COSV52230952; COSMIC: COSV52230952;