7-76514065-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_001347684.2(UPK3B):c.660T>C(p.Ser220=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000241 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: UPK3B NM_001347684.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.244

Genes affected

UPK3B (HGNC:21444): (uroplakin 3B) UPK3B is a minor component of the apical plaques of mammalian urothelium that binds and dimerizes with uroplakin-1b (UPK1B; MIM 602380), one of the major conserved urothelium membrane proteins. The other major conserved integral membrane proteins of urothelial plaques are UPK1A (MIM 611557), UPK2 (MIM 611558), and UPK3A (MIM 611559) (Deng et al., 2002 [PubMed 12446744]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.004109174).
• BP6: Variant 7-76514065-T-C is Benign according to our data. Variant chr7-76514065-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2212086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.244 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UPK3B	NM_001347684.2	c.660T>C	p.Ser220=	synonymous_variant	5/6	ENST00000334348.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UPK3B	ENST00000334348.8	c.660T>C	p.Ser220=	synonymous_variant	5/6	2	NM_001347684.2	P1
UPK3B	ENST00000257632.9	c.745T>C	p.Tyr249His	missense_variant	3/4	2
UPK3B	ENST00000394849.1	c.580T>C	p.Tyr194His	missense_variant	4/5	2
UPK3B	ENST00000469114.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00981

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000422 AC: 106 AN: 251438 Hom.: 0 AF XY: 0.000368 AC XY: 50 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00824

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000237 AC: 346 AN: 1461782 Hom.: 0 Cov.: 32 AF XY: 0.000246 AC XY: 179 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00896

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.000546

GnomAD4 genome AF: 0.000283 AC: 43 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74410

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00981

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000494 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000296 AC: 36

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

UPK3B: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	5.7
Dann	Benign	0.96
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.40	T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;N;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.61	N;N
REVEL	Benign	0.15
Sift	Benign	0.35	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.0	B;B
Vest4		0.16
MVP		0.014
ClinPred		0.011	T
GERP RS		1.3
Varity_R		0.039

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: rs141154955; hg19: chr7-76143382;