chr22-45287423-G-C

Position:

• chr22-45287423-G-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.460G>C​(p.Ala154Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.771 in 1,605,230 control chromosomes in the GnomAD database, including 478,033 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (46680 hom., cov: 32)
  • Exomes 𝑓: 0.77 (431353 hom.)
• Consequence: UPK3A NM_006953.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.651

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 (MetaRNN=2.0466093E-6).
• BP6: Variant 22-45287423-G-C is Benign according to our data. Variant chr22-45287423-G-C is described in ClinVar as [Benign]. Clinvar id is 341977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-45287423-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UPK3A	NM_006953.4	c.460G>C	p.Ala154Pro	missense_variant	3/6	ENST00000216211.9
UPK3A	NM_001167574.2	c.208+1327G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UPK3A	ENST00000216211.9	c.460G>C	p.Ala154Pro	missense_variant	3/6	1	NM_006953.4	P1
UPK3A	ENST00000396082.2	c.208+1327G>C		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.783 AC: 119083 AN: 152022 Hom.: 46641 Cov.: 32

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.869

Gnomad AMR AF: 0.807

Gnomad ASJ AF: 0.822

Gnomad EAS AF: 0.737

Gnomad SAS AF: 0.750

Gnomad FIN AF: 0.739

Gnomad MID AF: 0.742

Gnomad NFE AF: 0.769

Gnomad OTH AF: 0.774

GnomAD3 exomes AF: 0.775 AC: 182045 AN: 234914 Hom.: 70652 AF XY: 0.772 AC XY: 98020 AN XY: 127010

Gnomad AFR exome AF: 0.809

Gnomad AMR exome AF: 0.842

Gnomad ASJ exome AF: 0.828

Gnomad EAS exome AF: 0.723

Gnomad SAS exome AF: 0.757

Gnomad FIN exome AF: 0.739

Gnomad NFE exome AF: 0.765

Gnomad OTH exome AF: 0.772

GnomAD4 exome AF: 0.770 AC: 1118791 AN: 1453088 Hom.: 431353 Cov.: 81 AF XY: 0.770 AC XY: 555722 AN XY: 722082

Gnomad4 AFR exome AF: 0.818

Gnomad4 AMR exome AF: 0.839

Gnomad4 ASJ exome AF: 0.830

Gnomad4 EAS exome AF: 0.767

Gnomad4 SAS exome AF: 0.761

Gnomad4 FIN exome AF: 0.741

Gnomad4 NFE exome AF: 0.766

Gnomad4 OTH exome AF: 0.774

GnomAD4 genome AF: 0.783 AC: 119181 AN: 152142 Hom.: 46680 Cov.: 32 AF XY: 0.782 AC XY: 58161 AN XY: 74362

Gnomad4 AFR AF: 0.815

Gnomad4 AMR AF: 0.807

Gnomad4 ASJ AF: 0.822

Gnomad4 EAS AF: 0.737

Gnomad4 SAS AF: 0.749

Gnomad4 FIN AF: 0.739

Gnomad4 NFE AF: 0.769

Gnomad4 OTH AF: 0.773

Alfa AF: 0.770 Hom.: 30863

Bravo AF: 0.793

TwinsUK AF: 0.770 AC: 2857

ALSPAC AF: 0.770 AC: 2966

ESP6500AA AF: 0.811 AC: 3573

ESP6500EA AF: 0.778 AC: 6689

ExAC AF: 0.764 AC: 92530

Asia WGS AF: 0.758 AC: 2637 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal hypodysplasia/aplasia 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.032
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	8.3
DANN	Benign	0.15
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0000020	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.092
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.047
MPC		0.23
ClinPred		0.0028	T
GERP RS		3.4
Varity_R		0.067
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1057353; hg19: chr22-45683304; COSMIC: COSV53414048;