22-45287223-C-A

Position:

• chr22-45287223-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_006953.4(UPK3A):​c.260C>A​(p.Ser87*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,614,222 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0053 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00071 (9 hom.)
• Consequence: UPK3A NM_006953.4 stop_gained
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.05

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 -16 ACMG points.

• BP6: Variant 22-45287223-C-A is Benign according to our data. Variant chr22-45287223-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 341972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0053 (807/152334) while in subpopulation AFR AF= 0.0174 (725/41562). AF 95% confidence interval is 0.0164. There are 3 homozygotes in gnomad4. There are 359 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 807 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UPK3A	NM_006953.4	c.260C>A	p.Ser87*	stop_gained	3/6	ENST00000216211.9	NP_008884.1
UPK3A	NM_001167574.2	c.208+1127C>A		intron_variant			NP_001161046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UPK3A	ENST00000216211.9	c.260C>A	p.Ser87*	stop_gained	3/6	1	NM_006953.4	ENSP00000216211.4
UPK3A	ENST00000396082.2	c.208+1127C>A		intron_variant		1		ENSP00000379391.2

Frequencies

GnomAD3 genomes AF: 0.00530 AC: 807 AN: 152216 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00155 AC: 391 AN: 251448 Hom.: 3 AF XY: 0.00117 AC XY: 159 AN XY: 135902

Gnomad AFR exome AF: 0.0185

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00327

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000709 AC: 1037 AN: 1461888 Hom.: 9 Cov.: 35 AF XY: 0.000634 AC XY: 461 AN XY: 727244

Gnomad4 AFR exome AF: 0.0191

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00348

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000151

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00530 AC: 807 AN: 152334 Hom.: 3 Cov.: 33 AF XY: 0.00482 AC XY: 359 AN XY: 74496

Gnomad4 AFR AF: 0.0174

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000899 Hom.: 2

Bravo AF: 0.00600

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00173 AC: 210

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

Renal hypodysplasia/aplasia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	0.043
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.34	N
Vest4		0.23
GERP RS		1.7

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: rs138918236; hg19: chr22-45683104;