22-45287094-A-T

Variant names:

• chr22-45287094-A-T
• rs2673087
• NM_006953.4:c.209-78A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006953.4(UPK3A):​c.209-78A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: UPK3A NM_006953.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.69
• Publications: 10 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UPK3A	NM_006953.4	MANE Select	c.209-78A>T		intron	N/A	NP_008884.1	O75631-1
	UPK3A	NM_001167574.2		c.208+998A>T		intron	N/A	NP_001161046.1	O75631-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UPK3A	ENST00000216211.9	TSL:1 MANE Select	c.209-78A>T		intron	N/A	ENSP00000216211.4	O75631-1
	UPK3A	ENST00000396082.2	TSL:1	c.208+998A>T		intron	N/A	ENSP00000379391.2	O75631-2
	UPK3A	ENST00000957030.1		c.209-78A>T		intron	N/A	ENSP00000627089.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447930 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 720916

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000301 AC: 1 AN: 33214

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 85600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4442

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105436

Other (OTH) AF: 0.00 AC: 0 AN: 59942

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 174282

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.24
DANN	Benign	0.53
PhyloP100		-2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2673087; hg19: chr22-45682975;