chr22-45295673-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006953.4(UPK3A):c.818C>T(p.Pro273Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,613,930 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0023 ( 6 hom. )

Consequence

UPK3A
NM_006953.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.162

Publications

10 publications found

Variant links:

Genes affected

UPK3A (HGNC:12580): (uroplakin 3A) This gene encodes a member of the uroplakin family, a group of transmembrane proteins that form complexes on the apical surface of the bladder epithelium. Mutations in this gene may be associated with renal adysplasia. Alternatively spliced transcript variants have been described.[provided by RefSeq, Nov 2009]

UPK3A Gene-Disease associations (from GenCC):

renal agenesis, unilateral
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
renal dysplasia
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
congenital anomaly of kidney and urinary tract
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

UPK3A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11264211).

BS2

High AC in GnomAd4 at 199 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPK3A	NM_006953.4 link	c.818C>T	p.Pro273Leu	missense_variant	Exon 6 of 6	ENST00000216211.9	NP_008884.1
UPK3A	NM_001167574.2 link	c.455C>T	p.Pro152Leu	missense_variant	Exon 4 of 4		NP_001161046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPK3A	ENST00000216211.9 link	c.818C>T	p.Pro273Leu	missense_variant	Exon 6 of 6	1	NM_006953.4	ENSP00000216211.4
UPK3A	ENST00000396082.2 link	c.455C>T	p.Pro152Leu	missense_variant	Exon 4 of 4	1		ENSP00000379391.2

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

199

AN:

151968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000532

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000852

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00235

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00123

AC:

307

AN:

250460

AF XY:

0.00123

show subpopulations

Gnomad AFR exome

AF:

0.000376

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.00213

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00232

AC:

3388

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00227

AC XY:

1652

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33480

American (AMR)

AF:

0.00112

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000281

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00288

AC:

3204

AN:

1112006

Other (OTH)

AF:

0.00166

AC:

100

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

212

423

635

846

1058

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

264

396

528

660

<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:

0.00131

AC:

199

AN:

152086

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.000531

AC:

AN:

41468

American (AMR)

AF:

0.000851

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5122

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00235

AC:

160

AN:

68012

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00196

Hom.:

Bravo

AF:

0.00135

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00121

AC:

147

EpiCase

AF:

0.00196

EpiControl

AF:

0.00202

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital anomalies of kidney and urinary tract 1

Uncertain:1

Jul 01, 2005

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

Renal hypodysplasia/aplasia 1

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

not provided

Uncertain:1

Dec 23, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

UPK3A-related disorder

Uncertain:1

Dec 19, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The UPK3A c.818C>T variant is predicted to result in the amino acid substitution p.Pro273Leu. This variant was reported to occur de novo in two individuals with renal dysplasia and vesicoureteral reflux (Jenkins et al 2005. PubMed ID: 15888565; Dopazo J et al 2016. PubMed ID: 26764160). This variant was also reported as a variant of uncertain significance in a patient with multicystic kidney dysplasia (Nicolaou N et al 2016. PubMed ID: 26489027). This variant is reported in 0.21% of alleles in individuals of European (Non-Finnish) descent in gnomAD which seems too common to be a primary cause of disease. Although we suspect this variant is benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

8.6

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.8

L;.

PhyloP100

0.16

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.3

N;D

REVEL

Uncertain

0.43

Sift

Benign

0.038

D;D

Sift4G

Benign

0.24

T;T

Vest4

0.15

ClinPred

0.0074

GERP RS

-0.42

Varity_R

0.038

gMVP

0.67

Mutation Taster

=34/66

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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