chrX-119851748-C-CTTTTTTTTT

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_080632.3(UPF3B):c.263+10_263+18dupAAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0083 ( 37 hom., 89 hem., cov: 0)

Exomes 𝑓: 0.0072 ( 70 hom. 283 hem. )

Failed GnomAD Quality Control

Consequence

UPF3B
NM_080632.3 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

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 -10 ACMG points.

BP6

Variant X-119851748-C-CTTTTTTTTT is Benign according to our data. Variant chrX-119851748-C-CTTTTTTTTT is described in ClinVar as [Likely_benign]. Clinvar id is 1563570.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00826 (530/64181) while in subpopulation EAS AF = 0.0594 (85/1431). AF 95% confidence interval is 0.0492. There are 37 homozygotes in GnomAd4. There are 89 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 37 XL gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.00826

AC:

530

AN:

64189

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0204

Gnomad AMI

AF:

0.00187

Gnomad AMR

AF:

0.0204

Gnomad ASJ

AF:

0.00200

Gnomad EAS

AF:

0.0592

Gnomad SAS

AF:

0.00717

Gnomad FIN

AF:

0.000655

Gnomad MID

AF:

0.0247

Gnomad NFE

AF:

0.00171

Gnomad OTH

AF:

0.0167

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00721

AC:

3502

AN:

485578

Hom.:

Cov.:

AF XY:

0.00202

AC XY:

283

AN XY:

140176

show subpopulations

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

African (AFR)

AF:

0.0162

AC:

118

AN:

7273

American (AMR)

AF:

0.0221

AC:

258

AN:

11685

Ashkenazi Jewish (ASJ)

AF:

0.00715

AC:

AN:

11189

East Asian (EAS)

AF:

0.0478

AC:

658

AN:

13763

South Asian (SAS)

AF:

0.00959

AC:

264

AN:

27536

European-Finnish (FIN)

AF:

0.00593

AC:

154

AN:

25981

Middle Eastern (MID)

AF:

0.00975

AC:

AN:

1538

European-Non Finnish (NFE)

AF:

0.00482

AC:

1758

AN:

364702

Other (OTH)

AF:

0.00899

AC:

197

AN:

21911

⚠️ 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: 0.302

Heterozygous variant carriers

219

439

658

878

1097

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.00826

AC:

530

AN:

64181

Hom.:

Cov.:

AF XY:

0.00781

AC XY:

AN XY:

11399

show subpopulations

African (AFR)

AF:

0.0204

AC:

259

AN:

12712

American (AMR)

AF:

0.0204

AC:

AN:

4405

Ashkenazi Jewish (ASJ)

AF:

0.00200

AC:

AN:

2000

East Asian (EAS)

AF:

0.0594

AC:

AN:

1431

South Asian (SAS)

AF:

0.00725

AC:

AN:

965

European-Finnish (FIN)

AF:

0.000655

AC:

AN:

1526

Middle Eastern (MID)

AF:

0.0267

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00171

AC:

AN:

39743

Other (OTH)

AF:

0.0165

AC:

AN:

788

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.00

Hom.:

585

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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