16-20353690-T-C

Position:

• chr16-20353690-T-C

Variant summary

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

The ENST00000570689.5(UMOD):​c.-40+2504A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 152,112 control chromosomes in the GnomAD database, including 1,814 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 (1814 hom., cov: 32)
• Consequence: UMOD ENST00000570689.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.411

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=-0.87).
• 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/exons	MANE	UniProt
UMOD	XM_011545938.1	c.-40+2504A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UMOD	ENST00000570689.5	c.-40+2504A>G		intron_variant		5		P2

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21286 AN: 151998 Hom.: 1812 Cov.: 32

Gnomad AFR AF: 0.0536

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.154

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

GnomAD4 genome AF: 0.140 AC: 21291 AN: 152112 Hom.: 1814 Cov.: 32 AF XY: 0.141 AC XY: 10482 AN XY: 74348

Gnomad4 AFR AF: 0.0537

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.137

Gnomad4 EAS AF: 0.0108

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.226

Gnomad4 NFE AF: 0.181

Gnomad4 OTH AF: 0.155

Alfa AF: 0.142 Hom.: 275

Bravo AF: 0.132

Asia WGS AF: 0.0850 AC: 297 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.8
DANN	Benign	0.53

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs28362063; hg19: chr16-20365012;