22-45284989-G-C

Variant names:

• chr22-45284989-G-C
• rs116162068
• NM_006953.4:c.-25G>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.-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
• Publications: 2 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

ENSG00000301739 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006953.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UPK3A	NM_006953.4	MANE Select	c.-25G>C		5_prime_UTR	Exon 1 of 6	NP_008884.1	O75631-1
	UPK3A	NM_001167574.2		c.-25G>C		5_prime_UTR	Exon 1 of 4	NP_001161046.1	O75631-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UPK3A	ENST00000216211.9	TSL:1 MANE Select	c.-25G>C		5_prime_UTR	Exon 1 of 6	ENSP00000216211.4	O75631-1
	UPK3A	ENST00000957030.1		c.-25G>C		5_prime_UTR	Exon 1 of 6	ENSP00000627089.1
	UPK3A	ENST00000938588.1		c.-25G>C		5_prime_UTR	Exon 1 of 3	ENSP00000608647.1

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

GnomAD2 exomes AF: 0.0340 AC: 4269 AN: 125414 AF XY: 0.0330

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 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

African (AFR) AF: 0.202 AC: 6232 AN: 30852

American (AMR) AF: 0.0228 AC: 808 AN: 35490

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 457 AN: 24950

East Asian (EAS) AF: 0.104 AC: 3680 AN: 35386

South Asian (SAS) AF: 0.0334 AC: 2630 AN: 78774

European-Finnish (FIN) AF: 0.00616 AC: 206 AN: 33426

Middle Eastern (MID) AF: 0.0413 AC: 168 AN: 4066

European-Non Finnish (NFE) AF: 0.0125 AC: 13407 AN: 1076180

Other (OTH) AF: 0.0334 AC: 1920 AN: 57450

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

African (AFR) AF: 0.192 AC: 7975 AN: 41546

American (AMR) AF: 0.0338 AC: 517 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3470

East Asian (EAS) AF: 0.102 AC: 530 AN: 5178

South Asian (SAS) AF: 0.0437 AC: 211 AN: 4828

European-Finnish (FIN) AF: 0.00640 AC: 68 AN: 10622

Middle Eastern (MID) AF: 0.0445 AC: 13 AN: 292

European-Non Finnish (NFE) AF: 0.0128 AC: 873 AN: 68002

Other (OTH) AF: 0.0520 AC: 110 AN: 2116

Alfa AF: 0.0143 Hom.: 19

Bravo AF: 0.0770

Asia WGS AF: 0.0800 AC: 277 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Renal hypodysplasia/aplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.5
DANN	Benign	0.87
PhyloP100		-0.32
PromoterAI		-0.081	Neutral
Mutation Taster		=297/3	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: rs116162068; hg19: chr22-45680870;