rs373938471

Variant names:

• chr19-35673538-T-C
• rs373938471
• NM_007000.4:c.461T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007000.4(UPK1A):​c.461T>C​(p.Met154Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000449 in 1,613,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: UPK1A NM_007000.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.48

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPK1A	NM_007000.4	c.461T>C	p.Met154Thr	missense_variant	Exon 5 of 8	ENST00000222275.3	NP_008931.1
UPK1A	NM_001281443.2	c.461T>C	p.Met154Thr	missense_variant	Exon 5 of 9		NP_001268372.1
UPK1A-AS1	NR_046420.1	n.-247A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPK1A	ENST00000222275.3	c.461T>C	p.Met154Thr	missense_variant	Exon 5 of 8	1	NM_007000.4	ENSP00000222275.2
UPK1A	ENST00000379013.6	c.461T>C	p.Met154Thr	missense_variant	Exon 4 of 8	1		ENSP00000368298.1
UPK1A-AS1	ENST00000443196.2	n.-234A>G		upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000273 AC: 68 AN: 248740 Hom.: 0 AF XY: 0.000333 AC XY: 45 AN XY: 135072

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000366

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000470 AC: 686 AN: 1461118 Hom.: 0 Cov.: 32 AF XY: 0.000493 AC XY: 358 AN XY: 726884

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000561

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74412

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000446 Hom.: 0

Bravo AF: 0.000317

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000382

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.461T>C (p.M154T) alteration is located in exon 4 (coding exon 4) of the UPK1A gene. This alteration results from a T to C substitution at nucleotide position 461, causing the methionine (M) at amino acid position 154 to be replaced by a threonine (T). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.;.;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.69	T;T;.;.
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.5	L;L;L;L
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.2	.;.;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0030	.;.;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.97	D;D;D;D
Vest4		0.95
MVP		0.64
MPC		0.62
ClinPred		0.55	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.82

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: rs373938471; hg19: chr19-36164440;