19-35675904-C-A

Variant names:

• chr19-35675904-C-A
• rs1247988635
• NM_007000.4:c.533C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007000.4(UPK1A):​c.533C>A​(p.Ala178Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: UPK1A NM_007000.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63

Genes affected

UPK1A (HGNC:12577): (uroplakin 1A) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is found in the asymmetrical unit membrane (AUM) where it can complex with other transmembrane 4 superfamily proteins. It may play a role in normal bladder epithelial physiology, possibly in regulating membrane permeability of superficial umbrella cells or in stabilizing the apical membrane through AUM/cytoskeletal interactions. The protein may also play a role in tumor suppression. Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21478146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPK1A	NM_007000.4	c.533C>A	p.Ala178Asp	missense_variant	Exon 6 of 8	ENST00000222275.3	NP_008931.1
UPK1A	NM_001281443.2	c.533C>A	p.Ala178Asp	missense_variant	Exon 6 of 9		NP_001268372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPK1A	ENST00000222275.3	c.533C>A	p.Ala178Asp	missense_variant	Exon 6 of 8	1	NM_007000.4	ENSP00000222275.2
UPK1A	ENST00000379013.6	c.533C>A	p.Ala178Asp	missense_variant	Exon 5 of 8	1		ENSP00000368298.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461608 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727102

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.533C>A (p.A178D) alteration is located in exon 5 (coding exon 5) of the UPK1A gene. This alteration results from a C to A substitution at nucleotide position 533, causing the alanine (A) at amino acid position 178 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.029	T;.;.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.65	T;T;.;.
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.0	N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.90	.;.;N;N
REVEL	Benign	0.22
Sift	Benign	0.42	.;.;T;T
Sift4G	Benign	0.55	T;D;D;T
Polyphen		0.27	B;P;P;B
Vest4		0.40
MutPred		0.28		Loss of methylation at R176 (P = 0.0648);Loss of methylation at R176 (P = 0.0648);Loss of methylation at R176 (P = 0.0648);Loss of methylation at R176 (P = 0.0648);
MVP		0.51
MPC		0.63
ClinPred		0.36	T
GERP RS		5.0
Varity_R		0.24
gMVP		0.48

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: rs1247988635; hg19: chr19-36166806;