rs145186308

chr22-45286090-G-Achr22-45286090-G-Cchr22-45286090-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006953.4(UPK3A):c.202G>A(p.Asp68Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000861 in 1,614,110 control chromosomes in the GnomAD database, including 2 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00088 (2 hom.)
• Consequence: UPK3A NM_006953.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.15

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017673671).
• BS2: High AC in GnomAd at 103 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UPK3A	NM_006953.4	c.202G>A	p.Asp68Asn	missense_variant	2/6	ENST00000216211.9
UPK3A	NM_001167574.2	c.202G>A	p.Asp68Asn	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UPK3A	ENST00000216211.9	c.202G>A	p.Asp68Asn	missense_variant	2/6	1	NM_006953.4	P1
UPK3A	ENST00000396082.2	c.202G>A	p.Asp68Asn	missense_variant	2/4	1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000513 AC: 129 AN: 251288 Hom.: 0 AF XY: 0.000493 AC XY: 67 AN XY: 135816

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000849

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000687

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000880 AC: 1286 AN: 1461818 Hom.: 2 Cov.: 32 AF XY: 0.000832 AC XY: 605 AN XY: 727202

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00122

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00100

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.000671 AC XY: 50 AN XY: 74468

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000663 Hom.: 0

Bravo AF: 0.000669

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000428 AC: 52

EpiCase AF: 0.000491

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal hypodysplasia/aplasia 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	17
Dann	Benign	0.96
DEOGEN2	Benign	0.079	T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.41	N;N
REVEL	Benign	0.097
Sift	Benign	0.24	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.017	B;B
Vest4		0.21
MVP		0.31
MPC		0.20
ClinPred		0.0055	T
GERP RS		2.8
Varity_R		0.043
gMVP		0.51

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

Other links and lift over

dbSNP: rs145186308; hg19: chr22-45681971; COSMIC: COSV53414918;