NM_006953.4:c.356T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I119S) has been classified as Uncertain significance.

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

Publications

7 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 721168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 583 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006953.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UPK3A	NM_006953.4	MANE Select	c.356T>C	p.Ile119Thr	missense	Exon 3 of 6	NP_008884.1	O75631-1
	UPK3A	NM_001167574.2		c.208+1223T>C		intron	N/A	NP_001161046.1	O75631-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UPK3A	ENST00000216211.9	TSL:1 MANE Select	c.356T>C	p.Ile119Thr	missense	Exon 3 of 6	ENSP00000216211.4	O75631-1
UPK3A	ENST00000396082.2	TSL:1	c.208+1223T>C		intron	N/A	ENSP00000379391.2	O75631-2
UPK3A	ENST00000957030.1		c.356T>C	p.Ile119Thr	missense	Exon 3 of 6	ENSP00000627089.1

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

GnomAD2 exomes

AF:

0.00188

AC:

472

AN:

251446

AF XY:

0.00151

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 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

African (AFR)

AF:

0.0111

AC:

372

AN:

33480

American (AMR)

AF:

0.000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00191

AC:

AN:

26136

East Asian (EAS)

AF:

0.00519

AC:

206

AN:

39700

South Asian (SAS)

AF:

0.00108

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000140

AC:

156

AN:

1112012

Other (OTH)

AF:

0.00230

AC:

139

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

148

222

296

370

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00383

AC:

583

AN:

152314

Hom.:

Cov.:

AF XY:

0.00356

AC XY:

265

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0109

AC:

454

AN:

41562

American (AMR)

AF:

0.00222

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.00772

AC:

AN:

5182

South Asian (SAS)

AF:

0.00207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68020

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

119

149

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:

0.00144

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Renal hypodysplasia/aplasia 1 (1)

UPK3A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

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

PhyloP100

0.45

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

Mutation Taster

=100/0

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over