rs11859916

Variant names:

• chr16-20339909-G-A
• rs11859916
• NM_003361.4:c.1577+1182C>T

Variant summary

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

The NM_003361.4(UMOD):​c.1577+1182C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 152,036 control chromosomes in the GnomAD database, including 3,875 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 0.20 (3875 hom., cov: 32)
• Consequence: UMOD NM_003361.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.208
• Publications: 9 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 = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UMOD	NM_003361.4	c.1577+1182C>T		intron_variant	Intron 7 of 10	ENST00000396138.9	NP_003352.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UMOD	ENST00000396138.9	c.1577+1182C>T		intron_variant	Intron 7 of 10	5	NM_003361.4	ENSP00000379442.5
UMOD	ENST00000396134.6	c.1676+1182C>T		intron_variant	Intron 8 of 11	2		ENSP00000379438.2
UMOD	ENST00000570689.5	c.1577+1182C>T		intron_variant	Intron 7 of 10	5		ENSP00000460548.1
UMOD	ENST00000570331.1	n.342+1182C>T		intron_variant	Intron 2 of 5	5

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29709 AN: 151918 Hom.: 3871 Cov.: 32

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.0897

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.193

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

GnomAD4 genome AF: 0.196 AC: 29733 AN: 152036 Hom.: 3875 Cov.: 32 AF XY: 0.194 AC XY: 14457 AN XY: 74340

African (AFR) AF: 0.376 AC: 15583 AN: 41424

American (AMR) AF: 0.175 AC: 2666 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 465 AN: 3464

East Asian (EAS) AF: 0.215 AC: 1109 AN: 5158

South Asian (SAS) AF: 0.130 AC: 625 AN: 4816

European-Finnish (FIN) AF: 0.0897 AC: 949 AN: 10580

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7729 AN: 68006

Other (OTH) AF: 0.190 AC: 402 AN: 2112

Alfa AF: 0.148 Hom.: 6556

Bravo AF: 0.213

Asia WGS AF: 0.201 AC: 700 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	2.6
DANN	Benign	0.74
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11859916; hg19: chr16-20351231;