19-35668486-A-G

Variant names:

Variant summary

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

The NM_007000.4(UPK1A):c.117A>G(p.Ile39Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000068 ( 0 hom. )

Consequence

UPK1A
NM_007000.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.835

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:

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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=0.14356822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPK1A	NM_007000.4 link	c.117A>G	p.Ile39Met	missense_variant	Exon 3 of 8	ENST00000222275.3	NP_008931.1	O00322-1
UPK1A	NM_001281443.2 link	c.117A>G	p.Ile39Met	missense_variant	Exon 3 of 9		NP_001268372.1	O00322-2
UPK1A-AS1	NR_046420.1 link	n.257T>C		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.117A>G	p.Ile39Met	missense_variant	Exon 3 of 8	1	NM_007000.4	ENSP00000222275.2	O00322-1
UPK1A	ENST00000379013.6 link	c.117A>G	p.Ile39Met	missense_variant	Exon 2 of 8	1		ENSP00000368298.1	O00322-2
UPK1A-AS1	ENST00000443196.2 link	n.270T>C		non_coding_transcript_exon_variant	Exon 2 of 2	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251438

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.117A>G (p.I39M) alteration is located in exon 2 (coding exon 2) of the UPK1A gene. This alteration results from a A to G substitution at nucleotide position 117, causing the isoleucine (I) at amino acid position 39 to be replaced by a methionine (M). 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

0.33

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

T;.;.;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.69

T;T;.;.

M_CAP

Benign

0.066

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.4

L;L;L;L

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.8

.;.;N;N

REVEL

Uncertain

0.51

Sift

Uncertain

0.0010

.;.;D;D

Sift4G

Uncertain

0.0090

D;D;D;D

Polyphen

0.15

B;B;B;B

Vest4

0.29

MutPred

0.58

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.24

MPC

0.66

ClinPred

0.26

GERP RS

-8.3

Varity_R

0.39

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over