NM_006953.4:c.818C>T

Variant names:

• chr22-45295673-C-T
• rs121918186
• NM_006953.4:c.818C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006953.4(UPK3A):​c.818C>T​(p.Pro273Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,613,930 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (6 hom.)
• Consequence: UPK3A NM_006953.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.162
• Publications: 10 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11264211).
• BS2: High AC in GnomAd4 at 199 AD gene.

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.818C>T	p.Pro273Leu	missense	Exon 6 of 6	NP_008884.1	O75631-1
	UPK3A	NM_001167574.2		c.455C>T	p.Pro152Leu	missense	Exon 4 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.818C>T	p.Pro273Leu	missense	Exon 6 of 6	ENSP00000216211.4	O75631-1
	UPK3A	ENST00000396082.2	TSL:1	c.455C>T	p.Pro152Leu	missense	Exon 4 of 4	ENSP00000379391.2	O75631-2
	UPK3A	ENST00000957030.1		c.884C>T	p.Pro295Leu	missense	Exon 6 of 6	ENSP00000627089.1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 199 AN: 151968 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000532

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00123 AC: 307 AN: 250460 AF XY: 0.00123

Gnomad AFR exome AF: 0.000376

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00213

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00232 AC: 3388 AN: 1461844 Hom.: 6 Cov.: 31 AF XY: 0.00227 AC XY: 1652 AN XY: 727228

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.00112 AC: 50 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.000281 AC: 15 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00288 AC: 3204 AN: 1112006

Other (OTH) AF: 0.00166 AC: 100 AN: 60396

GnomAD4 genome AF: 0.00131 AC: 199 AN: 152086 Hom.: 0 Cov.: 31 AF XY: 0.00114 AC XY: 85 AN XY: 74342

African (AFR) AF: 0.000531 AC: 22 AN: 41468

American (AMR) AF: 0.000851 AC: 13 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00235 AC: 160 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00196 Hom.: 1

Bravo AF: 0.00135

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00121 AC: 147

EpiCase AF: 0.00196

EpiControl AF: 0.00202

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital anomalies of kidney and urinary tract 1 (1)
-	1	-	not provided (1)
-	1	-	Renal hypodysplasia/aplasia 1 (1)
-	1	-	UPK3A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	8.6
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.16
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.43
Sift	Benign	0.038	D
Sift4G	Benign	0.24	T
Polyphen		0.061	B
Vest4		0.15
MVP		0.61
MPC		0.18
ClinPred		0.0074	T
GERP RS		-0.42
Varity_R		0.038
gMVP		0.67
Mutation Taster		=34/66	disease causing

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: rs121918186; hg19: chr22-45691554;