rs1555487528

chr16-20348745-TGCGCCAGTACTCGTCCAGGGTGCGGTG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM4 PP5_Very_Strong

The NM_003361.4(UMOD):c.529_555del(p.His177_Arg185del) variant causes a inframe deletion change. 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:4 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 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_003361.4
• 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	UniProt
UMOD	NM_003361.4	c.529_555del	p.His177_Arg185del	inframe_deletion	3/11	ENST00000396138.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UMOD	ENST00000396138.9	c.529_555del	p.His177_Arg185del	inframe_deletion	3/11	5	NM_003361.4	P2
UMOD	ENST00000396134.6	c.628_654del	p.His210_Arg218del	inframe_deletion	4/12	2		A2
UMOD	ENST00000570689.5	c.529_555del	p.His177_Arg185del	inframe_deletion	3/11	5		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:4 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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 03, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	Common pathogenic variant -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -

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;