22-45287222-T-G

Position:

chr22-45287222-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006953.4(UPK3A):c.259T>G(p.Ser87Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,614,166 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0053 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00071 ( 9 hom. )

Consequence

UPK3A
NM_006953.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.144

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004951656).

BP6

Variant 22-45287222-T-G is Benign according to our data. Variant chr22-45287222-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 341971.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 = 0.0053 (807/152276) while in subpopulation AFR AF= 0.0174 (725/41558). AF 95% confidence interval is 0.0164. There are 3 homozygotes in gnomad4. There are 359 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 807 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UPK3A	NM_006953.4 linkuse as main transcript	c.259T>G	p.Ser87Ala	missense_variant	3/6	ENST00000216211.9	NP_008884.1	O75631-1
UPK3A	NM_001167574.2 linkuse as main transcript	c.208+1126T>G		intron_variant			NP_001161046.1	O75631-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UPK3A	ENST00000216211.9 linkuse as main transcript	c.259T>G	p.Ser87Ala	missense_variant	3/6	1	NM_006953.4	ENSP00000216211.4		O75631-1
UPK3A	ENST00000396082.2 linkuse as main transcript	c.208+1126T>G		intron_variant		1		ENSP00000379391.2		O75631-2

Frequencies

GnomAD3 genomes

AF:

0.00530

AC:

807

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0175

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00156

AC:

391

AN:

251444

Hom.:

AF XY:

0.00117

AC XY:

159

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.0185

Gnomad AMR exome

AF:

0.000925

Gnomad ASJ exome

AF:

0.00327

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000149

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000709

AC:

1037

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000634

AC XY:

461

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0191

Gnomad4 AMR exome

AF:

0.000917

Gnomad4 ASJ exome

AF:

0.00348

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000151

Gnomad4 OTH exome

AF:

0.00136

GnomAD4 genome

AF:

0.00530

AC:

807

AN:

152276

Hom.:

Cov.:

AF XY:

0.00482

AC XY:

359

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0174

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000893

Hom.:

Bravo

AF:

0.00600

ESP6500AA

AF:

0.0134

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00173

AC:

210

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Renal hypodysplasia/aplasia 1

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.30

DANN

Benign

0.89

DEOGEN2

Benign

0.079

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.38

MetaRNN

Benign

0.0050

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.5

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.69

REVEL

Benign

0.030

Sift

Benign

0.28

Sift4G

Benign

0.098

Polyphen

0.011

Vest4

0.021

MVP

0.35

MPC

0.15

ClinPred

0.00086

GERP RS

1.3

Varity_R

0.053

gMVP

0.31

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over