X-119851748-CTTTTTTT-CTTTTTTTTTTTTTTTTTTT

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_080632.3(UPF3B):c.263+7_263+18dupAAAAAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 93 hom., 182 hem., cov: 0)

Exomes 𝑓: 0.025 ( 144 hom. 1343 hem. )

Failed GnomAD Quality Control

Consequence

UPF3B
NM_080632.3 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0650

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

syndromic X-linked intellectual disability 14
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
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

UPF3B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant X-119851748-C-CTTTTTTTTTTTT is Benign according to our data. Variant chrX-119851748-C-CTTTTTTTTTTTT is described in ClinVar as [Likely_benign]. Clinvar id is 212547.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 = 0.0164 (1049/64143) while in subpopulation AFR AF = 0.0379 (481/12688). AF 95% confidence interval is 0.0351. There are 93 homozygotes in GnomAd4. There are 182 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 93 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF3B	NM_080632.3 link	c.263+7_263+18dupAAAAAAAAAAAA		intron_variant	Intron 2 of 10	ENST00000276201.7	NP_542199.1	Q9BZI7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPF3B	ENST00000276201.7 link	c.263+18_263+19insAAAAAAAAAAAA		intron_variant	Intron 2 of 10	1	NM_080632.3	ENSP00000276201.3		Q9BZI7-1
UPF3B	ENST00000345865.6 link	c.263+18_263+19insAAAAAAAAAAAA		intron_variant	Intron 2 of 9	1		ENSP00000245418.2		Q9BZI7-2

Frequencies

GnomAD3 genomes

AF:

0.0163

AC:

1048

AN:

64151

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0380

Gnomad AMI

AF:

0.00562

Gnomad AMR

AF:

0.0127

Gnomad ASJ

AF:

0.00499

Gnomad EAS

AF:

0.0132

Gnomad SAS

AF:

0.0113

Gnomad FIN

AF:

0.00262

Gnomad MID

AF:

0.0247

Gnomad NFE

AF:

0.0111

Gnomad OTH

AF:

0.0283

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0252

AC:

11807

AN:

468932

Hom.:

144

Cov.:

AF XY:

0.00994

AC XY:

1343

AN XY:

135060

show subpopulations

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

African (AFR)

AF:

0.0448

AC:

315

AN:

7026

American (AMR)

AF:

0.0611

AC:

678

AN:

11101

Ashkenazi Jewish (ASJ)

AF:

0.0302

AC:

324

AN:

10712

East Asian (EAS)

AF:

0.0761

AC:

1031

AN:

13541

South Asian (SAS)

AF:

0.0331

AC:

874

AN:

26389

European-Finnish (FIN)

AF:

0.0195

AC:

486

AN:

24872

Middle Eastern (MID)

AF:

0.0311

AC:

AN:

1478

European-Non Finnish (NFE)

AF:

0.0211

AC:

7436

AN:

352962

Other (OTH)

AF:

0.0296

AC:

617

AN:

20851

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.318

Heterozygous variant carriers

694

1389

2083

2778

3472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

272

408

544

680

<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:

0.0164

AC:

1049

AN:

64143

Hom.:

Cov.:

AF XY:

0.0160

AC XY:

182

AN XY:

11397

show subpopulations

African (AFR)

AF:

0.0379

AC:

481

AN:

12688

American (AMR)

AF:

0.0132

AC:

AN:

4408

Ashkenazi Jewish (ASJ)

AF:

0.00499

AC:

AN:

2004

East Asian (EAS)

AF:

0.0132

AC:

AN:

1437

South Asian (SAS)

AF:

0.0114

AC:

AN:

965

European-Finnish (FIN)

AF:

0.00262

AC:

AN:

1526

Middle Eastern (MID)

AF:

0.0267

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0111

AC:

439

AN:

39720

Other (OTH)

AF:

0.0280

AC:

AN:

786

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0330

Hom.:

585

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 25, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Syndromic X-linked intellectual disability 14

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.065

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over