22-45287235-A-T

Position:

• chr22-45287235-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006953.4(UPK3A):​c.272A>T​(p.Gln91Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0024 in 1,614,198 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (40 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (34 hom.)
• Consequence: UPK3A NM_006953.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.01

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=0.0038101673).
• BP6: Variant 22-45287235-A-T is Benign according to our data. Variant chr22-45287235-A-T is described in ClinVar as [Benign]. Clinvar id is 903368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0124 (1896/152316) while in subpopulation AFR AF= 0.0438 (1820/41560). AF 95% confidence interval is 0.0421. There are 40 homozygotes in gnomad4. There are 912 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1896 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UPK3A	NM_006953.4	c.272A>T	p.Gln91Leu	missense_variant	3/6	ENST00000216211.9	NP_008884.1
UPK3A	NM_001167574.2	c.208+1139A>T		intron_variant			NP_001161046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UPK3A	ENST00000216211.9	c.272A>T	p.Gln91Leu	missense_variant	3/6	1	NM_006953.4	ENSP00000216211.4
UPK3A	ENST00000396082.2	c.208+1139A>T		intron_variant		1		ENSP00000379391.2

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1891 AN: 152198 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.0438

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00333 AC: 838 AN: 251472 Hom.: 16 AF XY: 0.00230 AC XY: 312 AN XY: 135908

Gnomad AFR exome AF: 0.0461

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00135 AC: 1972 AN: 1461882 Hom.: 34 Cov.: 35 AF XY: 0.00115 AC XY: 837 AN XY: 727246

Gnomad4 AFR exome AF: 0.0475

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.00250

GnomAD4 genome AF: 0.0124 AC: 1896 AN: 152316 Hom.: 40 Cov.: 33 AF XY: 0.0122 AC XY: 912 AN XY: 74478

Gnomad4 AFR AF: 0.0438

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.00175 Hom.: 4

Bravo AF: 0.0137

ESP6500AA AF: 0.0438 AC: 193

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00407 AC: 494

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal hypodysplasia/aplasia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

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	0.16
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.069
Eigen_PC	Benign	0.050
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.10
Sift	Benign	0.43	T
Sift4G	Benign	0.24	T
Polyphen		0.88	P
Vest4		0.36
MVP		0.47
MPC		0.48
ClinPred		0.045	T
GERP RS		5.5
Varity_R		0.086
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs6006979; hg19: chr22-45683116;