19-35668476-C-T

Variant names:

• chr19-35668476-C-T
• rs1968034664
• NM_007000.4:c.107C>T

Variant summary

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

The NM_007000.4(UPK1A):​c.107C>T​(p.Ala36Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,854 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (1 hom.)
• Consequence: UPK1A NM_007000.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.86

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, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPK1A	NM_007000.4	c.107C>T	p.Ala36Val	missense_variant	Exon 3 of 8	ENST00000222275.3	NP_008931.1
UPK1A	NM_001281443.2	c.107C>T	p.Ala36Val	missense_variant	Exon 3 of 9		NP_001268372.1
UPK1A-AS1	NR_046420.1	n.267G>A		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPK1A	ENST00000222275.3	c.107C>T	p.Ala36Val	missense_variant	Exon 3 of 8	1	NM_007000.4	ENSP00000222275.2
UPK1A	ENST00000379013.6	c.107C>T	p.Ala36Val	missense_variant	Exon 2 of 8	1		ENSP00000368298.1
UPK1A-AS1	ENST00000443196.2	n.280G>A		non_coding_transcript_exon_variant	Exon 2 of 2	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461854 Hom.: 1 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.107C>T (p.A36V) alteration is located in exon 2 (coding exon 2) of the UPK1A gene. This alteration results from a C to T substitution at nucleotide position 107, causing the alanine (A) at amino acid position 36 to be replaced by a valine (V). 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	0.65
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T;.;.;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T;T;.;.
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.4	L;L;L;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.9	.;.;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0030	.;.;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.79
MutPred		0.61		Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);
MVP		0.62
MPC		0.75
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.62
gMVP		0.91

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: rs1968034664; hg19: chr19-36159378;