chr16-20356368-G-T

Variant names:

• chr16-20356368-G-T
• rs12917707
• ENST00000863071.1:c.-277C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000863071.1(UMOD):​c.-277C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 152,638 control chromosomes in the GnomAD database, including 1,791 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 (1788 hom., cov: 32)
  • Exomes 𝑓: 0.081 (3 hom.)
• Consequence: UMOD ENST00000863071.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.24
• Publications: 118 publications found

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]

UMOD Gene-Disease associations (from GenCC):

• autosomal dominant medullary cystic kidney disease with or without hyperuricemia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• glomerulocystic kidney disease with hyperuricemia and isosthenuria

  Inheritance: AD Classification: DEFINITIVE Submitted by: Laboratory for Molecular Medicine
• familial juvenile hyperuricemic nephropathy type 1

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant medullary cystic kidney disease with hyperuricemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000863071.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMOD	ENST00000863071.1		c.-277C>A		5_prime_UTR	Exon 1 of 11	ENSP00000533130.1
	UMOD	ENST00000570689.5	TSL:5	c.-214C>A		upstream_gene	N/A	ENSP00000460548.1	P07911-1
	UMOD	ENST00000863072.1		c.-198C>A		upstream_gene	N/A	ENSP00000533131.1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20935 AN: 152114 Hom.: 1786 Cov.: 32

Gnomad AFR AF: 0.0465

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.149

GnomAD4 exome AF: 0.0813 AC: 33 AN: 406 Hom.: 3 AF XY: 0.0940 AC XY: 22 AN XY: 234

African (AFR) AF: 0.00 AC: 0 AN: 10

American (AMR) AF: 0.00 AC: 0 AN: 8

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 30

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.214 AC: 6 AN: 28

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0865 AC: 27 AN: 312

Other (OTH) AF: 0.00 AC: 0 AN: 12

GnomAD4 genome AF: 0.138 AC: 20937 AN: 152232 Hom.: 1788 Cov.: 32 AF XY: 0.139 AC XY: 10341 AN XY: 74428

African (AFR) AF: 0.0465 AC: 1933 AN: 41556

American (AMR) AF: 0.166 AC: 2532 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 474 AN: 3470

East Asian (EAS) AF: 0.0108 AC: 56 AN: 5184

South Asian (SAS) AF: 0.140 AC: 675 AN: 4826

European-Finnish (FIN) AF: 0.227 AC: 2401 AN: 10598

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.180 AC: 12241 AN: 67992

Other (OTH) AF: 0.151 AC: 318 AN: 2112

Alfa AF: 0.157 Hom.: 6612

Bravo AF: 0.129

Asia WGS AF: 0.0850 AC: 294 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Benign	0.75
PhyloP100		2.2
PromoterAI		0.0054	Neutral

Splicing

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

Other links and lift over

dbSNP: rs12917707; hg19: chr16-20367690;