Genetic Variant UPF3B:c.263+15_263+18dupAAAA (chrX-119851748-C-CTTTT) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_080632.3(UPF3B):c.263+15_263+18dupAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.024 ( 137 hom., 326 hem., cov: 0)

Exomes 𝑓: 0.0016 ( 7 hom. 25 hem. )

Failed GnomAD Quality Control

Consequence

UPF3B
NM_080632.3 intron

Scores

Not classified

Clinical Significance

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: Likely_benign. The variant received -2 ACMG points.

BP6

Variant X-119851748-C-CTTTT is Benign according to our data. Variant chrX-119851748-C-CTTTT is described in ClinVar as [Benign]. Clinvar id is 1590336.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF3B	NM_080632.3 link	c.263+15_263+18dupAAAA		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+19insAAAA		intron_variant	Intron 2 of 10	1	NM_080632.3	ENSP00000276201.3		Q9BZI7-1
UPF3B	ENST00000345865.6 link	c.263+18_263+19insAAAA		intron_variant	Intron 2 of 9	1		ENSP00000245418.2		Q9BZI7-2

Frequencies

GnomAD3 genomes

AF:

0.0240

AC:

1539

AN:

64239

Hom.:

137

Cov.:

show subpopulations

Gnomad AFR

AF:

0.112

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00102

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0123

Gnomad NFE

AF:

0.000226

Gnomad OTH

AF:

0.0193

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00155

AC:

767

AN:

494684

Hom.:

Cov.:

AF XY:

0.000172

AC XY:

AN XY:

145192

show subpopulations

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

African (AFR)

AF:

0.0696

AC:

489

AN:

7030

American (AMR)

AF:

0.00437

AC:

AN:

12141

Ashkenazi Jewish (ASJ)

AF:

0.0000877

AC:

AN:

11404

East Asian (EAS)

AF:

0.00174

AC:

AN:

14960

South Asian (SAS)

AF:

0.000383

AC:

AN:

28729

European-Finnish (FIN)

AF:

0.000114

AC:

AN:

26355

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1574

European-Non Finnish (NFE)

AF:

0.000200

AC:

AN:

370190

Other (OTH)

AF:

0.00493

AC:

110

AN:

22301

⚠️ 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: 0.352

Heterozygous variant carriers

131

175

219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0240

AC:

1539

AN:

64231

Hom.:

137

Cov.:

AF XY:

0.0286

AC XY:

326

AN XY:

11399

show subpopulations

African (AFR)

AF:

0.112

AC:

1426

AN:

12741

American (AMR)

AF:

0.0197

AC:

AN:

4411

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2002

East Asian (EAS)

AF:

0.00

AC:

AN:

1437

South Asian (SAS)

AF:

0.00104

AC:

AN:

965

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1526

Middle Eastern (MID)

AF:

0.0133

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000226

AC:

AN:

39750

Other (OTH)

AF:

0.0190

AC:

AN:

788

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

108

144

180

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:

0.00

Hom.:

585

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Syndromic X-linked intellectual disability 14

Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: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

(source)

Splicing

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

Publications

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X-119851748-CTTTTTTT-CTTTTTTTTTTT

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