22-45289121-A-G

Variant names:

• chr22-45289121-A-G
• rs1135360
• NM_006953.4:c.549A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006953.4(UPK3A):​c.549A>G​(p.Ser183Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,613,364 control chromosomes in the GnomAD database, including 181,954 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (26658 hom., cov: 31)
  • Exomes 𝑓: 0.45 (155296 hom.)
• Consequence: UPK3A NM_006953.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -6.86
• Publications: 22 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 22-45289121-A-G is Benign according to our data. Variant chr22-45289121-A-G is described in ClinVar as Benign. ClinVar VariationId is 341981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPK3A	NM_006953.4	c.549A>G	p.Ser183Ser	synonymous_variant	Exon 4 of 6	ENST00000216211.9	NP_008884.1
UPK3A	NM_001167574.2	c.208+3025A>G		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.549A>G	p.Ser183Ser	synonymous_variant	Exon 4 of 6	1	NM_006953.4	ENSP00000216211.4
UPK3A	ENST00000396082.2	c.208+3025A>G		intron_variant	Intron 2 of 3	1		ENSP00000379391.2

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85353 AN: 151894 Hom.: 26594 Cov.: 31

Gnomad AFR AF: 0.842

Gnomad AMI AF: 0.393

Gnomad AMR AF: 0.511

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.688

Gnomad SAS AF: 0.577

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.525

GnomAD2 exomes AF: 0.499 AC: 125270 AN: 250872 AF XY: 0.494

Gnomad AFR exome AF: 0.847

Gnomad AMR exome AF: 0.494

Gnomad ASJ exome AF: 0.411

Gnomad EAS exome AF: 0.698

Gnomad FIN exome AF: 0.465

Gnomad NFE exome AF: 0.418

Gnomad OTH exome AF: 0.470

GnomAD4 exome AF: 0.453 AC: 661583 AN: 1461352 Hom.: 155296 Cov.: 49 AF XY: 0.454 AC XY: 329709 AN XY: 726968

African (AFR) AF: 0.856 AC: 28668 AN: 33480

American (AMR) AF: 0.498 AC: 22279 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 10767 AN: 26132

East Asian (EAS) AF: 0.671 AC: 26640 AN: 39692

South Asian (SAS) AF: 0.555 AC: 47903 AN: 86252

European-Finnish (FIN) AF: 0.458 AC: 24361 AN: 53162

Middle Eastern (MID) AF: 0.492 AC: 2836 AN: 5768

European-Non Finnish (NFE) AF: 0.422 AC: 468831 AN: 1111766

Other (OTH) AF: 0.485 AC: 29298 AN: 60380

GnomAD4 genome AF: 0.562 AC: 85489 AN: 152012 Hom.: 26658 Cov.: 31 AF XY: 0.565 AC XY: 41980 AN XY: 74294

African (AFR) AF: 0.842 AC: 34929 AN: 41466

American (AMR) AF: 0.511 AC: 7807 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1404 AN: 3464

East Asian (EAS) AF: 0.689 AC: 3549 AN: 5154

South Asian (SAS) AF: 0.577 AC: 2779 AN: 4816

European-Finnish (FIN) AF: 0.466 AC: 4928 AN: 10572

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.419 AC: 28455 AN: 67958

Other (OTH) AF: 0.530 AC: 1115 AN: 2102

Alfa AF: 0.452 Hom.: 34453

Bravo AF: 0.576

Asia WGS AF: 0.678 AC: 2354 AN: 3478

EpiCase AF: 0.415

EpiControl AF: 0.422

ClinVar

Significance: Benign

Submissions summary: Benign:5

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 13, 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 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.027
DANN	Benign	0.43
PhyloP100		-6.9
Mutation Taster		=100/0	polymorphism (auto)

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: rs1135360; hg19: chr22-45685002; COSMIC: COSV53414471;