7-76515074-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001347684.2(UPK3B):c.701C>T(p.Pro234Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000762 in 1,444,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P234P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: UPK3B NM_001347684.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0740

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15951866).
• BP6: Variant 7-76515074-C-T is Benign according to our data. Variant chr7-76515074-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3186823.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UPK3B	NM_001347684.2	c.701C>T	p.Pro234Leu	missense_variant	6/6	ENST00000334348.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UPK3B	ENST00000334348.8	c.701C>T	p.Pro234Leu	missense_variant	6/6	2	NM_001347684.2	P1
UPK3B	ENST00000257632.9	c.786C>T	p.Pro262=	synonymous_variant	4/4	2
UPK3B	ENST00000394849.1	c.621C>T	p.Pro207=	synonymous_variant	5/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000762 AC: 11 AN: 1444138 Hom.: 0 Cov.: 31 AF XY: 0.00000837 AC XY: 6 AN XY: 716928

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000634

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.0051	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.98	D;D;D;D;D;D
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.062
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Vest4		0.22
MutPred		0.38		Gain of helix (P = 0.0078);
MVP		0.32
ClinPred		0.31	T
GERP RS		3.2
gMVP		0.57

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: rs1812684428; hg19: chr7-76144391; COSMIC: COSV99991089; COSMIC: COSV99991089;