rs6497476

Positions:

• chr16-20353459-T-C

Variant summary

Our verdict is Benign. Variant got -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

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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UMOD	XM_011545938.1	c.-39-2683A>G		intron_variant			XP_011544240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UMOD	ENST00000570689.5	c.-39-2683A>G		intron_variant		5		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

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.0602

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0623

Gnomad4 SAS AF: 0.114

Gnomad4 FIN AF: 0.000943

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.0350

Alfa AF: 0.0533 Hom.: 97

Bravo AF: 0.0639

Asia WGS AF: 0.0970 AC: 337 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.60

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs6497476; hg19: chr16-20364781;