Genetic Variant UPK3B:p.Tyr153Cys (chr7-76511879-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001347684.2(UPK3B):c.458A>G(p.Tyr153Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,392,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

UPK3B
NM_001347684.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.30

Variant links:

Genes affected

UPK3B (HGNC:21444): (uroplakin 3B) UPK3B is a minor component of the apical plaques of mammalian urothelium that binds and dimerizes with uroplakin-1b (UPK1B; MIM 602380), one of the major conserved urothelium membrane proteins. The other major conserved integral membrane proteins of urothelial plaques are UPK1A (MIM 611557), UPK2 (MIM 611558), and UPK3A (MIM 611559) (Deng et al., 2002 [PubMed 12446744]).[supplied by OMIM, Mar 2008]

UPK3B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.050201237).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPK3B	NM_001347684.2 link	c.458A>G	p.Tyr153Cys	missense_variant	Exon 3 of 6	ENST00000334348.8	NP_001334613.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPK3B	ENST00000334348.8 link	c.458A>G	p.Tyr153Cys	missense_variant	Exon 3 of 6	2	NM_001347684.2	ENSP00000334938.3		Q9BT76-3

Frequencies

GnomAD3 genomes

AF:

0.000499

AC:

AN:

150424

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00178

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000662

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:

0.00

Gnomad OTH

AF:

0.000487

GnomAD3 exomes

AF:

0.000295

AC:

AN:

47524

Hom.:

AF XY:

0.000292

AC XY:

AN XY:

23984

show subpopulations

Gnomad AFR exome

AF:

0.00335

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000636

AC:

AN:

1241714

Hom.:

Cov.:

AF XY:

0.0000432

AC XY:

AN XY:

602336

show subpopulations

Gnomad4 AFR exome

AF:

0.00260

Gnomad4 AMR exome

AF:

0.000102

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000202

Gnomad4 OTH exome

AF:

0.0000967

GnomAD4 genome

AF:

0.000492

AC:

AN:

150546

Hom.:

Cov.:

AF XY:

0.000436

AC XY:

AN XY:

73458

show subpopulations

Gnomad4 AFR

AF:

0.00175

Gnomad4 AMR

AF:

0.0000661

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000481

Alfa

AF:

0.000674

Hom.:

Bravo

AF:

0.000654

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 22, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.623A>G (p.Y208C) alteration is located in exon 2 (coding exon 2) of the UPK3B gene. This alteration results from a A to G substitution at nucleotide position 623, causing the tyrosine (Y) at amino acid position 208 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Benign

-0.0073

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.27

.;T;.

Eigen

Benign

-0.041

Eigen_PC

Benign

-0.0033

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.86

D;T;T

M_CAP

Uncertain

0.094

MetaRNN

Benign

0.050

T;T;T

MetaSVM

Uncertain

-0.091

MutationAssessor

Benign

0.0

.;N;.

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-8.6

D;D;D

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

D;T;T

Sift4G

Pathogenic

0.0

D;T;T

Polyphen

0.023, 0.15

.;B;B

Vest4

0.72

MVP

0.55

ClinPred

0.13

GERP RS

5.2

Varity_R

0.21

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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