chr22-45286090-G-C

Variant names:

• chr22-45286090-G-C
• rs145186308
• NM_006953.4:c.202G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_006953.4(UPK3A):​c.202G>C​(p.Asp68His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D68N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: UPK3A NM_006953.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.15
• Publications: 5 publications found

Genes affected

UPK3A (HGNC:12580): (uroplakin 3A) This gene encodes a member of the uroplakin family, a group of transmembrane proteins that form complexes on the apical surface of the bladder epithelium. Mutations in this gene may be associated with renal adysplasia. Alternatively spliced transcript variants have been described.[provided by RefSeq, Nov 2009]

UPK3A Gene-Disease associations (from GenCC):

• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal dysplasia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• congenital anomaly of kidney and urinary tract

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28494906).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006953.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UPK3A	NM_006953.4	MANE Select	c.202G>C	p.Asp68His	missense	Exon 2 of 6	NP_008884.1
	UPK3A	NM_001167574.2		c.202G>C	p.Asp68His	missense	Exon 2 of 4	NP_001161046.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UPK3A	ENST00000216211.9	TSL:1 MANE Select	c.202G>C	p.Asp68His	missense	Exon 2 of 6	ENSP00000216211.4
	UPK3A	ENST00000396082.2	TSL:1	c.202G>C	p.Asp68His	missense	Exon 2 of 4	ENSP00000379391.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251288 AF XY: 0.00

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461820 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727204

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111986

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.202G>C (p.D68H) alteration is located in exon 2 (coding exon 2) of the UPK3A gene. This alteration results from a G to C substitution at nucleotide position 202, causing the aspartic acid (D) at amino acid position 68 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.21
Sift	Benign	0.030	D
Sift4G	Uncertain	0.043	D
Polyphen		0.97	D
Vest4		0.43
MutPred		0.28		Loss of sheet (P = 0.0817)
MVP		0.43
MPC		0.76
ClinPred		0.76	D
GERP RS		2.8
Varity_R		0.069
gMVP		0.63
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs145186308; hg19: chr22-45681971;