rs1555487528

Positions:

• chr16-20348745-TGCGCCAGTACTCGTCCAGGGTGCGGTG-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM4 PP5_Very_Strong

The NM_003361.4(UMOD):​c.529_555del​(p.His177_Arg185del) variant causes a inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: UMOD NM_003361.4 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 5.81

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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a region_of_interest D10C (size 119) in uniprot entity UROM_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) 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.
• PP5: Variant 16-20348745-TGCGCCAGTACTCGTCCAGGGTGCGGTG-T is Pathogenic according to our data. Variant chr16-20348745-TGCGCCAGTACTCGTCCAGGGTGCGGTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 12254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UMOD	NM_003361.4	c.529_555del	p.His177_Arg185del	inframe_deletion	3/11	ENST00000396138.9	NP_003352.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UMOD	ENST00000396138.9	c.529_555del	p.His177_Arg185del	inframe_deletion	3/11	5	NM_003361.4	ENSP00000379442	P2
UMOD	ENST00000396134.6	c.628_654del	p.His210_Arg218del	inframe_deletion	4/12	2		ENSP00000379438	A2
UMOD	ENST00000570689.5	c.529_555del	p.His177_Arg185del	inframe_deletion	3/11	5		ENSP00000460548	P2

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

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial juvenile hyperuricemic nephropathy type 1 Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2002	- -
not provided, no classification provided	literature only	GeneReviews	-	Common pathogenic variant -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 03, 2022	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 14, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 12254). This variant has been observed in individual(s) with familial juvenile hyperuricaemic nephropathy (PMID: 12471200). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.529_555del, results in the deletion of 9 amino acid(s) of the UMOD protein (p.His177_Arg185del), but otherwise preserves the integrity of the reading frame. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2016	- -

UMOD-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 16, 2024

The UMOD c.529_555del27 variant is predicted to result in an in-frame deletion (p.His177_Arg185del). In a linkage mapping and sequencing study, this variant has been reported to completely segregate with disease in a large multigenerational family affected by familial juvenile hyperuricaemic nephropathy (Family 1 in Hart et al. 2002. PubMed ID: 12471200). In addition, this variant has also been reported in patients with UMOD-related diseases (Table S3 of Bleyer et al. 2022. PubMed ID: 35325889; Table S1 of Olinger et al. 2020. PubMed ID: 32450155; Wilson et al. 2020. PubMed ID: 35372954). In the ClinVar database, this variant has been interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/12254/). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555487528; hg19: chr16-20360067;