NM_006953.4:c.-25G>C

Variant names:

• chr22-45284989-G-C
• rs116162068
• NM_006953.4:c.-25G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006953.4(UPK3A):​c.-25G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0261 in 1,528,842 control chromosomes in the GnomAD database, including 1,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (838 hom., cov: 33)
  • Exomes 𝑓: 0.021 (1128 hom.)
• Consequence: UPK3A NM_006953.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.321

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 22-45284989-G-C is Benign according to our data. Variant chr22-45284989-G-C is described in ClinVar as [Benign]. Clinvar id is 341968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPK3A	NM_006953.4	c.-25G>C		5_prime_UTR_variant	Exon 1 of 6	ENST00000216211.9	NP_008884.1
UPK3A	NM_001167574.2	c.-25G>C		5_prime_UTR_variant	Exon 1 of 4		NP_001161046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPK3A	ENST00000216211	c.-25G>C		5_prime_UTR_variant	Exon 1 of 6	1	NM_006953.4	ENSP00000216211.4
UPK3A	ENST00000396082.2	c.-25G>C		upstream_gene_variant		1		ENSP00000379391.2

Frequencies

GnomAD3 genomes AF: 0.0681 AC: 10356 AN: 152160 Hom.: 837 Cov.: 33

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0339

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.0441

Gnomad FIN AF: 0.00640

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.0525

GnomAD3 exomes AF: 0.0340 AC: 4269 AN: 125414 Hom.: 227 AF XY: 0.0330 AC XY: 2269 AN XY: 68756

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.0208

Gnomad ASJ exome AF: 0.0176

Gnomad EAS exome AF: 0.114

Gnomad SAS exome AF: 0.0331

Gnomad FIN exome AF: 0.00544

Gnomad NFE exome AF: 0.0110

Gnomad OTH exome AF: 0.0238

GnomAD4 exome AF: 0.0214 AC: 29508 AN: 1376574 Hom.: 1128 Cov.: 31 AF XY: 0.0212 AC XY: 14412 AN XY: 679096

Gnomad4 AFR exome AF: 0.202

Gnomad4 AMR exome AF: 0.0228

Gnomad4 ASJ exome AF: 0.0183

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.0334

Gnomad4 FIN exome AF: 0.00616

Gnomad4 NFE exome AF: 0.0125

Gnomad4 OTH exome AF: 0.0334

GnomAD4 genome AF: 0.0681 AC: 10366 AN: 152268 Hom.: 838 Cov.: 33 AF XY: 0.0670 AC XY: 4990 AN XY: 74466

Gnomad4 AFR AF: 0.192

Gnomad4 AMR AF: 0.0338

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.102

Gnomad4 SAS AF: 0.0437

Gnomad4 FIN AF: 0.00640

Gnomad4 NFE AF: 0.0128

Gnomad4 OTH AF: 0.0520

Alfa AF: 0.0143 Hom.: 19

Bravo AF: 0.0770

Asia WGS AF: 0.0800 AC: 277 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal hypodysplasia/aplasia 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.5
DANN	Benign	0.87

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: rs116162068; hg19: chr22-45680870;