NM_006953.4:c.*107T>C

Variant names:

• chr22-45295826-T-C
• rs558490093
• NM_006953.4:c.*107T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006953.4(UPK3A):​c.*107T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,334,734 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (9 hom.)
• Consequence: UPK3A NM_006953.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2 B:1
• Conservation: PhyloP100: -0.110
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS2: High AC in GnomAd4 at 238 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPK3A	NM_006953.4	c.*107T>C		3_prime_UTR_variant	Exon 6 of 6	ENST00000216211.9	NP_008884.1
UPK3A	NM_001167574.2	c.*107T>C		3_prime_UTR_variant	Exon 4 of 4		NP_001161046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPK3A	ENST00000216211.9	c.*107T>C		3_prime_UTR_variant	Exon 6 of 6	1	NM_006953.4	ENSP00000216211.4
UPK3A	ENST00000396082.2	c.*107T>C		downstream_gene_variant		1		ENSP00000379391.2

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152198 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00250 AC: 2958 AN: 1182418 Hom.: 9 Cov.: 16 AF XY: 0.00253 AC XY: 1510 AN XY: 597986

African (AFR) AF: 0.000410 AC: 11 AN: 26860

American (AMR) AF: 0.000409 AC: 16 AN: 39128

Ashkenazi Jewish (ASJ) AF: 0.000334 AC: 8 AN: 23970

East Asian (EAS) AF: 0.00 AC: 0 AN: 36426

South Asian (SAS) AF: 0.000936 AC: 73 AN: 77970

European-Finnish (FIN) AF: 0.000705 AC: 29 AN: 41154

Middle Eastern (MID) AF: 0.000253 AC: 1 AN: 3952

European-Non Finnish (NFE) AF: 0.00309 AC: 2721 AN: 881714

Other (OTH) AF: 0.00193 AC: 99 AN: 51244

GnomAD4 genome AF: 0.00156 AC: 238 AN: 152316 Hom.: 1 Cov.: 33 AF XY: 0.00129 AC XY: 96 AN XY: 74490

African (AFR) AF: 0.000433 AC: 18 AN: 41578

American (AMR) AF: 0.000785 AC: 12 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4832

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00288 AC: 196 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00180 Hom.: 0

Bravo AF: 0.00173

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal hypodysplasia/aplasia 1 Uncertain:2

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. -

Jul 01, 2005

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

UPK3A-related disorder Benign:1

Oct 19, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.52
DANN	Benign	0.60
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs558490093; hg19: chr22-45691707;