chr22-45287423-G-C

Variant names:

• chr22-45287423-G-C
• rs1057353
• NM_006953.4:c.460G>C

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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
• Publications: 30 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 -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 VariationId is 341977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPK3A	NM_006953.4	c.460G>C	p.Ala154Pro	missense_variant	Exon 3 of 6	ENST00000216211.9	NP_008884.1
UPK3A	NM_001167574.2	c.208+1327G>C		intron_variant	Intron 2 of 3		NP_001161046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPK3A	ENST00000216211.9	c.460G>C	p.Ala154Pro	missense_variant	Exon 3 of 6	1	NM_006953.4	ENSP00000216211.4
UPK3A	ENST00000396082.2	c.208+1327G>C		intron_variant	Intron 2 of 3	1		ENSP00000379391.2

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

GnomAD2 exomes AF: 0.775 AC: 182045 AN: 234914 AF XY: 0.772

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 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

African (AFR) AF: 0.818 AC: 27285 AN: 33344

American (AMR) AF: 0.839 AC: 35974 AN: 42862

Ashkenazi Jewish (ASJ) AF: 0.830 AC: 21475 AN: 25870

East Asian (EAS) AF: 0.767 AC: 30197 AN: 39378

South Asian (SAS) AF: 0.761 AC: 64821 AN: 85226

European-Finnish (FIN) AF: 0.741 AC: 39079 AN: 52754

Middle Eastern (MID) AF: 0.752 AC: 4325 AN: 5754

European-Non Finnish (NFE) AF: 0.766 AC: 849182 AN: 1107874

Other (OTH) AF: 0.774 AC: 46453 AN: 60026

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

African (AFR) AF: 0.815 AC: 33819 AN: 41494

American (AMR) AF: 0.807 AC: 12345 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.822 AC: 2854 AN: 3472

East Asian (EAS) AF: 0.737 AC: 3813 AN: 5174

South Asian (SAS) AF: 0.749 AC: 3612 AN: 4824

European-Finnish (FIN) AF: 0.739 AC: 7813 AN: 10566

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.769 AC: 52285 AN: 68002

Other (OTH) AF: 0.773 AC: 1632 AN: 2112

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

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
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
PhyloP100		0.65
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1057353; hg19: chr22-45683304; COSMIC: COSV53414048;