rs6497476

Variant names:

• chr16-20353459-T-C
• rs6497476
• ENST00000570689.5:c.-39-2683A>G

Variant summary

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

The ENST00000570689.5(UMOD):​c.-39-2683A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0566 in 152,232 control chromosomes in the GnomAD database, including 628 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 0.057 (628 hom., cov: 32)
• Consequence: UMOD ENST00000570689.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.228
• Publications: 10 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: AD, Unknown 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000570689.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMOD	ENST00000570689.5	TSL:5	c.-39-2683A>G		intron	N/A	ENSP00000460548.1

Frequencies

GnomAD3 genomes AF: 0.0566 AC: 8604 AN: 152114 Hom.: 628 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0602

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0620

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.0349

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

GnomAD4 genome AF: 0.0566 AC: 8621 AN: 152232 Hom.: 628 Cov.: 32 AF XY: 0.0585 AC XY: 4351 AN XY: 74436

African (AFR) AF: 0.161 AC: 6700 AN: 41512

American (AMR) AF: 0.0602 AC: 920 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0623 AC: 323 AN: 5182

South Asian (SAS) AF: 0.114 AC: 552 AN: 4822

European-Finnish (FIN) AF: 0.000943 AC: 10 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68034

Other (OTH) AF: 0.0350 AC: 74 AN: 2114

Alfa AF: 0.0574 Hom.: 108

Bravo AF: 0.0639

Asia WGS AF: 0.0970 AC: 337 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.60
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs6497476; hg19: chr16-20364781;