rs142862074

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 16/22 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.08

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 id is 536851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-119841119-C-T is described in Lovd as [Likely_benign].

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 FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF3B	NM_080632.3 link	c.764G>A	p.Arg255Lys	missense_variant	Exon 7 of 11	ENST00000276201.7	NP_542199.1	Q9BZI7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UPF3B	ENST00000276201.7 link	c.764G>A	p.Arg255Lys	missense_variant	Exon 7 of 11	1	NM_080632.3	ENSP00000276201.3	Q9BZI7-1
UPF3B	ENST00000345865.6 link	c.764G>A	p.Arg255Lys	missense_variant	Exon 7 of 10	1		ENSP00000245418.2	Q9BZI7-2
UPF3B	ENST00000478840.1 link	n.352G>A		non_coding_transcript_exon_variant	Exon 4 of 6	3

Frequencies

GnomAD3 genomes

AF:

0.00200

AC:

223

AN:

111554

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.000153

AC XY:

AN XY:

359629

show subpopulations

Gnomad4 AFR exome

AF:

0.00753

AC:

198

AN:

26309

Gnomad4 AMR exome

AF:

0.000343

AC:

AN:

34995

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

19343

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

30149

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

53490

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

40360

Gnomad4 NFE exome

AF:

0.00000357

AC:

AN:

839319

Gnomad4 Remaining exome

AF:

0.000435

AC:

AN:

45955

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00199

AC:

222

AN:

111608

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

AN XY:

33816

show subpopulations

Gnomad4 AFR

AF:

0.00689

AC:

0.00689252

AN:

0.00689252

Gnomad4 AMR

AF:

0.000573

AC:

0.000573175

AN:

0.000573175

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000188

AC:

0.000018842

AN:

0.000018842

Gnomad4 OTH

AF:

0.00197

AC:

0.00197498

AN:

0.00197498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00127

Hom.:

Bravo

AF:

0.00211

ESP6500AA

AF:

0.00834

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000700

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Syndromic X-linked intellectual disability 14

Benign:1

Dec 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

May 25, 2017

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

UPF3B-related disorder

Benign:1

Sep 06, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

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

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.016

T;.

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.2

L;L

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.44

N;N

REVEL

Benign

0.15

Sift

Benign

0.63

T;T

Sift4G

Benign

0.85

T;T

Polyphen

0.064

B;B

Vest4

0.12

MVP

0.47

MPC

0.43

ClinPred

0.0056

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over