16-20356323-C-T

Variant names:

• chr16-20356323-C-T
• rs12922822
• ENST00000570689.5:c.-169G>A

Variant summary

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

The ENST00000570689.5(UMOD):​c.-169G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 152,590 control chromosomes in the GnomAD database, including 1,808 homozygotes. 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: 𝑓 0.14 (1805 hom., cov: 32)
  • Exomes 𝑓: 0.10 (3 hom.)
• Consequence: UMOD ENST00000570689.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.452

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=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UMOD	XM_011545938.1	c.-169G>A		upstream_gene_variant			XP_011544240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UMOD	ENST00000570689.5	c.-169G>A		upstream_gene_variant		5		ENSP00000460548.1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 21047 AN: 152118 Hom.: 1803 Cov.: 32

Gnomad AFR AF: 0.0476

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.150

GnomAD4 exome AF: 0.105 AC: 37 AN: 354 Hom.: 3 Cov.: 0 AF XY: 0.119 AC XY: 27 AN XY: 226

Gnomad4 AFR exome AF: 0.100

Gnomad4 AMR exome AF: 0.333

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.136

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.138 AC: 21049 AN: 152236 Hom.: 1805 Cov.: 32 AF XY: 0.140 AC XY: 10386 AN XY: 74426

Gnomad4 AFR AF: 0.0477

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.137

Gnomad4 EAS AF: 0.0106

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.226

Gnomad4 NFE AF: 0.181

Gnomad4 OTH AF: 0.152

Alfa AF: 0.105 Hom.: 261

Bravo AF: 0.130

Asia WGS AF: 0.0840 AC: 293 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	10
DANN	Benign	0.67

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs12922822; hg19: chr16-20367645;