NM_003361.4:c.317G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_003361.4(UMOD):c.317G>A(p.Cys106Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C106F) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

UMOD
NM_003361.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 4.13

Publications

10 publications found

Variant links:

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

UMOD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_003361.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-20348984-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94129.

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 or without hyperuricemia, familial juvenile hyperuricemic nephropathy type 1, glomerulocystic kidney disease with hyperuricemia and isosthenuria, autosomal dominant medullary cystic kidney disease with hyperuricemia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 16-20348984-C-T is Pathogenic according to our data. Variant chr16-20348984-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 807521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UMOD	NM_003361.4 link	c.317G>A	p.Cys106Tyr	missense_variant	Exon 3 of 11	ENST00000396138.9	NP_003352.2	P07911-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UMOD	ENST00000396138.9 link	c.317G>A	p.Cys106Tyr	missense_variant	Exon 3 of 11	5	NM_003361.4	ENSP00000379442.5		P07911-1X6RBG4
UMOD	ENST00000396134.6 link	c.416G>A	p.Cys139Tyr	missense_variant	Exon 4 of 12	2		ENSP00000379438.2		P07911-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1421900

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

703700

African (AFR)

AF:

0.00

AC:

AN:

32558

American (AMR)

AF:

0.00

AC:

AN:

38744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25424

East Asian (EAS)

AF:

0.00

AC:

AN:

37350

South Asian (SAS)

AF:

0.00

AC:

AN:

81398

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1091942

Other (OTH)

AF:

0.00

AC:

AN:

58930

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial juvenile hyperuricemic nephropathy type 1

Pathogenic:5

Feb 14, 2019

Yale Center for Mendelian Genomics, Yale University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 07, 2024

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 23, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000807521). A different missense change at the same codon (p.Cys106Phe) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000094129). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

May 26, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine (exon 3). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (2 heterozygotes, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (2nd EGF-like domain; NCBI, Decipher). (N) 0704 - Comparable variant has low previous evidence for pathogenicity. A different variant in the same codon resulting in a change to phenylalanine has also been reported pathogenic (ClinVar, PMID: 29204651). (P) 0803 - Low previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in patients with Uromodulin-associated kidney disease (UAKD) (PMID: 20172860) and chronic kidney disease, tubulointerstitial kidney disease, gout and hyperuricaemic nephropathy (PMID: 30773290, PMID: 31509055). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Cysteines in UMOD gene are involved in structurally important disulphide bridges. The interruption of these bonds has been proven for multiple variants affecting cysteines, leading to impaired trafficking of the protein to the cell membrane (PMID: 23748428, PMID: 28781372). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) – Benign -

Jan 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant medullary cystic kidney disease with or without hyperuricemia

Pathogenic:2

Jan 05, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change in UMOD is predicted to replace cysteine with tyrosine at codon 106, p.(Cys106Tyr). The cysteine residue is highly conserved (100 vertebrates, Multiz Alignments), and disrupts a cysteine residue involved in a disulphide bond in the calcium-binding EGF domain (PMID: 23748428). There is a large physicochemical difference between cysteine and tyrosine. This variant is absent from the population database gnomAD v4.0. This variant has been reported in individuals with tubulointerstitial nephropathy and segregates with disease (PMID: 20172860, 29204651, 31822006, 32954071; ClinVar: SCV001449472.1, SCV003841615.1, SCV001149980.1; Royal Melbourne Hospital). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.906). Another missense variant c.317G>T p.(Cys106Phe) in the same codon has been classified as likely pathogenic/pathogenic for tubulointerstitial nephropathy (ClinVar Variation ID: 94129; PMID: 32274456, 32926855). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM1, PS4_Moderate, PM5, PP1_Moderate, PP3, PM2_Supporting -

Sep 15, 2017

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This patient is heterozygous for a c.317G>A p.(Cys106Tyr) in the UMOD gene. To our knowledge, this variant has not been reported in any population databases (i.e. ExAC, ESP or dbSNP). The c.317G>A p.(Cys106Tyr) has been reported in a patient with uromodulin associated kidney disease (Zaucke et al. Hum Mol Genet 2010; 19(10): 1985-1997). The p.Cys106 residue is a highly conserved amino acid (up to 12 species) and there is also a large physicochemical difference between the wild type cysteine and mutant tyrosine. In silico analysis (Alamut Visual v2.8.1) using SIFT, PolyPhen2 and MutationTaster all predict that this variant is likely to be pathogenic. This variant is considered to be likely pathogenic according to the ACMG guidelines. -

not provided

Pathogenic:1

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

UMOD: PM1:Strong, PM2, PM5, PS4:Moderate -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

.;.;.;.;T;.;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

D;D;D;.;D;D;D;T

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

4.1

.;.;H;H;.;.;.;.

PhyloP100

4.1

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-4.5

D;D;D;.;.;.;.;.

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;T;D;.;.;.;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D;.;.;D;D

Polyphen

1.0

.;.;D;D;.;.;.;.

Vest4

0.85

MutPred

0.93

.;.;Gain of phosphorylation at C106 (P = 0.0128);Gain of phosphorylation at C106 (P = 0.0128);.;Gain of phosphorylation at C106 (P = 0.0128);.;.;

MVP

0.94

MPC

2.4

ClinPred

1.0

GERP RS

5.5

Varity_R

0.98

gMVP

1.0

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over