rs878855325

Variant names:

• chr16-20349012-CTTCGGGGCAGA-AGGAGGCGG
• rs878855325
• NM_003361.4:c.278_289delTCTGCCCCGAAGinsCCGCCTCCT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM2 PM4_Supporting PP2 PP5_Very_Strong

The NM_003361.4(UMOD):​c.278_289delTCTGCCCCGAAGinsCCGCCTCCT​(p.Val93_Gly97delinsAlaAlaSerCys) variant causes a missense, disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004812539: The variant demonstrates deficient intracellular trafficking associated with endoplasmic reticulum retention and reduced secretion in multiple in vitro functional assays with limited validation (PMID:22034507, 32954071)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: UMOD NM_003361.4 missense, disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.16
• Publications: 1 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: Unknown, AD 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: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004812539: The variant demonstrates deficient intracellular trafficking associated with endoplasmic reticulum retention and reduced secretion in multiple in vitro functional assays with limited validation (PMID: 22034507, 32954071).; SCV001427125: "This variant has moderate functional evidence supporting abnormal protein function. Functional studies show that this variant causes trafficking defects and endoplasmic reticulum retention, resulting in premature intracellular polymerization (ClinVar, PMID: 22034507, 25436415);"; SCV002762400: Published functional studies in HEK293 cells demonstrate that c.278_289del12ins effects protein maturation and results in ER retention (Smith et al., 2011), and functional studies in tsA 201 cells demonstrate that c.278_289del12ins results in intracellular protein aggregation and premature polymerization (Stewart et al., 2015); PMID: 25436415, 22034507, 14531790, 32274456, 32939031, 20301530
• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_003361.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_003361.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 69 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 0.99836 (below the threshold of 3.09). Trascript score misZ: 0.48416 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant medullary cystic kidney disease with hyperuricemia, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, familial juvenile hyperuricemic nephropathy type 1, glomerulocystic kidney disease with hyperuricemia and isosthenuria.
• PP5: Variant 16-20349012-CTTCGGGGCAGA-AGGAGGCGG is Pathogenic according to our data. Variant chr16-20349012-CTTCGGGGCAGA-AGGAGGCGG is described in ClinVar as Pathogenic. ClinVar VariationId is 242346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003361.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMOD	NM_003361.4	MANE Select	c.278_289delTCTGCCCCGAAGinsCCGCCTCCT	p.Val93_Gly97delinsAlaAlaSerCys	missense disruptive_inframe_deletion	N/A	NP_003352.2	P07911-1
	UMOD	NM_001378234.1		c.278_289delTCTGCCCCGAAGinsCCGCCTCCT	p.Val93_Gly97delinsAlaAlaSerCys	missense disruptive_inframe_deletion	N/A	NP_001365163.1
	UMOD	NM_001378235.1		c.278_289delTCTGCCCCGAAGinsCCGCCTCCT	p.Val93_Gly97delinsAlaAlaSerCys	missense disruptive_inframe_deletion	N/A	NP_001365164.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMOD	ENST00000396138.9	TSL:5 MANE Select	c.278_289delTCTGCCCCGAAGinsCCGCCTCCT	p.Val93_Gly97delinsAlaAlaSerCys	missense disruptive_inframe_deletion	N/A	ENSP00000379442.5	P07911-1
	UMOD	ENST00000396134.6	TSL:2	c.377_388delTCTGCCCCGAAGinsCCGCCTCCT	p.Val126_Gly130delinsAlaAlaSerCys	missense disruptive_inframe_deletion	N/A	ENSP00000379438.2	P07911-5
	UMOD	ENST00000863077.1		c.440_451delTCTGCCCCGAAGinsCCGCCTCCT	p.Val147_Gly151delinsAlaAlaSerCys	missense disruptive_inframe_deletion	N/A	ENSP00000533136.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Familial juvenile hyperuricemic nephropathy type 1 (4)
2	-	-	Autosomal dominant medullary cystic kidney disease with or without hyperuricemia (2)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2
Mutation Taster		=0/200	disease causing

Splicing

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

Other links and lift over

dbSNP: rs878855325; hg19: chr16-20360334;