19-35673488-C-G

Variant names:

• chr19-35673488-C-G
• rs780429103
• NM_007000.4:c.411C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007000.4(UPK1A):​c.411C>G​(p.Ser137Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 152,082 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: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: UPK1A NM_007000.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.755

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2745456).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPK1A	NM_007000.4	c.411C>G	p.Ser137Arg	missense_variant	Exon 5 of 8	ENST00000222275.3	NP_008931.1
UPK1A	NM_001281443.2	c.411C>G	p.Ser137Arg	missense_variant	Exon 5 of 9		NP_001268372.1
UPK1A-AS1	NR_046420.1	n.-197G>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPK1A	ENST00000222275.3	c.411C>G	p.Ser137Arg	missense_variant	Exon 5 of 8	1	NM_007000.4	ENSP00000222275.2
UPK1A	ENST00000379013.6	c.411C>G	p.Ser137Arg	missense_variant	Exon 4 of 8	1		ENSP00000368298.1
UPK1A-AS1	ENST00000443196.2	n.-184G>C		upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74272

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.411C>G (p.S137R) alteration is located in exon 4 (coding exon 4) of the UPK1A gene. This alteration results from a C to G substitution at nucleotide position 411, causing the serine (S) at amino acid position 137 to be replaced by an arginine (R). 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	0.31
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T;.;.;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.74	T;T;.;.
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.0	N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.62	.;.;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.18	.;.;T;T
Sift4G	Benign	0.11	T;D;D;T
Polyphen		0.17	B;D;D;B
Vest4		0.58
MutPred		0.50		Gain of phosphorylation at T140 (P = 0.0941);Gain of phosphorylation at T140 (P = 0.0941);Gain of phosphorylation at T140 (P = 0.0941);Gain of phosphorylation at T140 (P = 0.0941);
MVP		0.36
MPC		0.57
ClinPred		0.62	D
GERP RS		-1.4
Varity_R		0.29
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs780429103; hg19: chr19-36164390;