rs13333226

Positions:

• chr16-20354332-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000570689.5(UMOD):​c.-40+1862T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 151,980 control chromosomes in the GnomAD database, including 4,388 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency: Genomes: 𝑓 0.23 (4388 hom., cov: 32)
• Consequence: UMOD ENST00000570689.5 intron
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: -0.649

Genes affected

UMOD (HGNC:12559): (uromodulin) The protein encoded by this gene is the most abundant protein in mammalian urine under physiological conditions. Its excretion in urine follows proteolytic cleavage of the ectodomain of its glycosyl phosphatidylinosital-anchored counterpart that is situated on the luminal cell surface of the loop of Henle. This protein may act as a constitutive inhibitor of calcium crystallization in renal fluids. Excretion of this protein in urine may provide defense against urinary tract infections caused by uropathogenic bacteria. Defects in this gene are associated with the renal disorders medullary cystic kidney disease-2 (MCKD2), glomerulocystic kidney disease with hyperuricemia and isosthenuria (GCKDHI), and familial juvenile hyperuricemic nephropathy (FJHN). Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UMOD	XM_011545938.1	c.-40+1862T>C		intron_variant			XP_011544240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UMOD	ENST00000570689.5	c.-40+1862T>C		intron_variant		5		ENSP00000460548.1

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35047 AN: 151860 Hom.: 4377 Cov.: 32

Gnomad AFR AF: 0.327

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.0737

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.212

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.231 AC: 35090 AN: 151980 Hom.: 4388 Cov.: 32 AF XY: 0.234 AC XY: 17361 AN XY: 74290

Gnomad4 AFR AF: 0.327

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.147

Gnomad4 EAS AF: 0.0736

Gnomad4 SAS AF: 0.285

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.183

Gnomad4 OTH AF: 0.214

Alfa AF: 0.186 Hom.: 4403

Bravo AF: 0.234

Asia WGS AF: 0.205 AC: 714 AN: 3478

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Essential hypertension Other:1

association, no assertion criteria provided

case-control

College of Pharmacy, University of Babylon

Jul 01, 2015

A case-control association study with enrolling individuals belonging to Arab ancestry from Babylon province, Iraq. The study enrolled 100 cases of well diagnosed essential hypertensive patients and 70 controls of carefully selected normotensive individuals. For genotyping, we designed and optimized ‘polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP)’ and ‘polymerase chain reaction amplification of multiple specific alleles (PAMSA)’ methods, and each sample was genotyped by the two methods to ensure precise genotyping. Concerning UMOD rs13333226, the results showed that allele A conferred an additional risk for essential hypertension with odds ratio 1.75 (C.I.1.03-2.96) (P =0.035), while the G allele represents a protective allele conferring a lesser susceptibility for hypertension (OR = 0.57, C.I. 0.33-0.96). The genotypic association under different inheritance models showed that the A allele was inherited as a recessive risk allele, the GG+AG to AA odd ratio equal to 2.17 (C.I. 1.14-4.11)( P = 0.022). When the association was tested in each gender, the association and odds ratio increased further in the males, in which the A allele recorded with an odds ratio of 3.28 (C.I. 1.43-7.50 ) and P value of 0.0035, while the females did not record any significant association. We concluded that the rs13333226 variant of the UMOD gene represents a genetic factor that can modulate the susceptibility to develop essential hypertension in males from Arab ancestry of Babylon province. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.88
DANN	Benign	0.60

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs13333226; hg19: chr16-20365654;