rs36060036

Positions:

• chr16-20350628-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003361.4(UMOD):​c.88+22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,613,248 control chromosomes in the GnomAD database, including 20,422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1514 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18908 hom.)
• Consequence: UMOD NM_003361.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.458

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 16-20350628-C-T is Benign according to our data. Variant chr16-20350628-C-T is described in ClinVar as [Benign]. Clinvar id is 1226888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UMOD	NM_003361.4	c.88+22G>A		intron_variant		ENST00000396138.9	NP_003352.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UMOD	ENST00000396138.9	c.88+22G>A		intron_variant		5	NM_003361.4	ENSP00000379442	P2

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18745 AN: 152088 Hom.: 1514 Cov.: 32

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.00540

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.129

GnomAD3 exomes AF: 0.139 AC: 34711 AN: 249662 Hom.: 2867 AF XY: 0.143 AC XY: 19282 AN XY: 135076

Gnomad AFR exome AF: 0.0243

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.00757

Gnomad SAS exome AF: 0.139

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.156 AC: 228156 AN: 1461042 Hom.: 18908 Cov.: 32 AF XY: 0.156 AC XY: 113384 AN XY: 726788

Gnomad4 AFR exome AF: 0.0256

Gnomad4 AMR exome AF: 0.137

Gnomad4 ASJ exome AF: 0.131

Gnomad4 EAS exome AF: 0.00335

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.219

Gnomad4 NFE exome AF: 0.166

Gnomad4 OTH exome AF: 0.145

GnomAD4 genome AF: 0.123 AC: 18734 AN: 152206 Hom.: 1514 Cov.: 32 AF XY: 0.126 AC XY: 9342 AN XY: 74408

Gnomad4 AFR AF: 0.0295

Gnomad4 AMR AF: 0.154

Gnomad4 ASJ AF: 0.135

Gnomad4 EAS AF: 0.00522

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.222

Gnomad4 NFE AF: 0.165

Gnomad4 OTH AF: 0.128

Alfa AF: 0.140 Hom.: 314

Bravo AF: 0.113

Asia WGS AF: 0.0710 AC: 248 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.82
DANN	Benign	0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs36060036; hg19: chr16-20361950;