19-35673295-C-T

Variant names:

• chr19-35673295-C-T
• rs868225923
• NM_007000.4:c.349C>T

Variant summary

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

The NM_007000.4(UPK1A):​c.349C>T​(p.His117Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: UPK1A NM_007000.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.00

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]

UPK1A-AS1 (HGNC:40603): (UPK1A antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPK1A	NM_007000.4	c.349C>T	p.His117Tyr	missense_variant	Exon 4 of 8	ENST00000222275.3	NP_008931.1
UPK1A	NM_001281443.2	c.349C>T	p.His117Tyr	missense_variant	Exon 4 of 9		NP_001268372.1
UPK1A-AS1	NR_046420.1	n.-4G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPK1A	ENST00000222275.3	c.349C>T	p.His117Tyr	missense_variant	Exon 4 of 8	1	NM_007000.4	ENSP00000222275.2
UPK1A	ENST00000379013.6	c.349C>T	p.His117Tyr	missense_variant	Exon 3 of 8	1		ENSP00000368298.1
UPK1A-AS1	ENST00000443196.2	n.10G>A		non_coding_transcript_exon_variant	Exon 1 of 2	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461782 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727186

Gnomad4 AFR exome AF: 0.0000597

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.349C>T (p.H117Y) alteration is located in exon 3 (coding exon 3) of the UPK1A gene. This alteration results from a C to T substitution at nucleotide position 349, causing the histidine (H) at amino acid position 117 to be replaced by a tyrosine (Y). 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	Uncertain	0.52
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T;.;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.82	T;T;.;.
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.3	L;L;L;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.46	.;.;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.47	.;.;T;T
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		0.98	D;D;D;D
Vest4		0.75
MutPred		0.54		Loss of disorder (P = 0.112);Loss of disorder (P = 0.112);Loss of disorder (P = 0.112);Loss of disorder (P = 0.112);
MVP		0.49
MPC		0.80
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.47
gMVP		0.69

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: rs868225923; hg19: chr19-36164197;