Genetic Variant UPK1A:p.Ser91Pro (chr19-35668640-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_007000.4(UPK1A):c.271T>C(p.Ser91Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,000 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: 6.8e-7 ( 0 hom. )

Consequence

UPK1A
NM_007000.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.00300

Variant links:

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 links:

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

UPK1A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.10925534).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPK1A	NM_007000.4 link	c.271T>C	p.Ser91Pro	missense_variant	Exon 3 of 8	ENST00000222275.3	NP_008931.1	O00322-1
UPK1A	NM_001281443.2 link	c.271T>C	p.Ser91Pro	missense_variant	Exon 3 of 9		NP_001268372.1	O00322-2
UPK1A-AS1	NR_046420.1 link	n.103A>G		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UPK1A	ENST00000222275.3 link	c.271T>C	p.Ser91Pro	missense_variant	Exon 3 of 8	1	NM_007000.4	ENSP00000222275.2	O00322-1
UPK1A	ENST00000379013.6 link	c.271T>C	p.Ser91Pro	missense_variant	Exon 2 of 8	1		ENSP00000368298.1	O00322-2
UPK1A-AS1	ENST00000443196.2 link	n.116A>G		non_coding_transcript_exon_variant	Exon 2 of 2	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461000

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726726

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.271T>C (p.S91P) alteration is located in exon 2 (coding exon 2) of the UPK1A gene. This alteration results from a T to C substitution at nucleotide position 271, causing the serine (S) at amino acid position 91 to be replaced by a proline (P). 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

0.10

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.025

T;.;.;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.53

T;T;.;.

M_CAP

Benign

0.0063

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N;N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.83

.;.;N;N

REVEL

Benign

0.23

Sift

Benign

0.23

.;.;T;T

Sift4G

Benign

0.31

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.17

MutPred

0.67

Loss of catalytic residue at S91 (P = 0.0069);Loss of catalytic residue at S91 (P = 0.0069);Loss of catalytic residue at S91 (P = 0.0069);Loss of catalytic residue at S91 (P = 0.0069);

MVP

0.27

MPC

0.24

ClinPred

0.051

GERP RS

0.65

Varity_R

0.26

gMVP

0.85

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over