22-45287319-T-C

Position:

chr22-45287319-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006953.4(UPK3A):c.356T>C(p.Ile119Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,614,208 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00073 ( 5 hom. )

Consequence

UPK3A
NM_006953.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.453

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033169687).

BP6

Variant 22-45287319-T-C is Benign according to our data. Variant chr22-45287319-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 721168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 583 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UPK3A	NM_006953.4 linkuse as main transcript	c.356T>C	p.Ile119Thr	missense_variant	3/6	ENST00000216211.9	NP_008884.1	O75631-1
UPK3A	NM_001167574.2 linkuse as main transcript	c.208+1223T>C		intron_variant			NP_001161046.1	O75631-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UPK3A	ENST00000216211.9 linkuse as main transcript	c.356T>C	p.Ile119Thr	missense_variant	3/6	1	NM_006953.4	ENSP00000216211.4		O75631-1
UPK3A	ENST00000396082.2 linkuse as main transcript	c.208+1223T>C		intron_variant		1		ENSP00000379391.2		O75631-2

Frequencies

GnomAD3 genomes

AF:

0.00382

AC:

581

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00770

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00188

AC:

472

AN:

251446

Hom.:

AF XY:

0.00151

AC XY:

205

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0102

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.0101

Gnomad SAS exome

AF:

0.00108

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000264

Gnomad OTH exome

AF:

0.000977

GnomAD4 exome

AF:

0.000731

AC:

1069

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000661

AC XY:

481

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0111

Gnomad4 AMR exome

AF:

0.000894

Gnomad4 ASJ exome

AF:

0.00191

Gnomad4 EAS exome

AF:

0.00519

Gnomad4 SAS exome

AF:

0.00108

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000140

Gnomad4 OTH exome

AF:

0.00230

GnomAD4 genome

AF:

0.00383

AC:

583

AN:

152314

Hom.:

Cov.:

AF XY:

0.00356

AC XY:

265

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0109

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00772

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.000922

Hom.:

Bravo

AF:

0.00432

ESP6500AA

AF:

0.0111

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00193

AC:

234

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Renal hypodysplasia/aplasia 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

UPK3A-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.067

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.099

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0033

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PrimateAI

Benign

0.29

PROVEAN

Benign

0.32

REVEL

Benign

0.036

Sift

Benign

0.27

Sift4G

Benign

0.14

Polyphen

0.044

Vest4

0.022

MVP

0.38

MPC

0.24

ClinPred

0.00076

GERP RS

3.3

Varity_R

0.036

gMVP

0.32

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

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