rs55772253

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_003361.4(UMOD):c.1372G>T(p.Val458Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,613,928 control chromosomes in the GnomAD database, including 509 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V458M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.016 ( 34 hom., cov: 31)

Exomes 𝑓: 0.022 ( 475 hom. )

Consequence

UMOD
NM_003361.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.96

Publications

17 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: Benign. The variant received -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.004376799).

BP6

Variant 16-20341296-C-A is Benign according to our data. Variant chr16-20341296-C-A is described in ClinVar as Benign. ClinVar VariationId is 290985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UMOD	NM_003361.4 link	c.1372G>T	p.Val458Leu	missense_variant	Exon 7 of 11	ENST00000396138.9	NP_003352.2	P07911-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UMOD	ENST00000396138.9 link	c.1372G>T	p.Val458Leu	missense_variant	Exon 7 of 11	5	NM_003361.4	ENSP00000379442.5	P07911-1X6RBG4
UMOD	ENST00000396134.6 link	c.1471G>T	p.Val491Leu	missense_variant	Exon 8 of 12	2		ENSP00000379438.2	P07911-5
UMOD	ENST00000570689.5 link	c.1372G>T	p.Val458Leu	missense_variant	Exon 7 of 11	5		ENSP00000460548.1	P07911-1
UMOD	ENST00000570331.1 link	n.137G>T		non_coding_transcript_exon_variant	Exon 2 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.0164

AC:

2487

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00447

Gnomad AMI

AF:

0.00769

Gnomad AMR

AF:

0.0200

Gnomad ASJ

AF:

0.0663

Gnomad EAS

AF:

0.000582

Gnomad SAS

AF:

0.0354

Gnomad FIN

AF:

0.0141

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0201

Gnomad OTH

AF:

0.0254

GnomAD2 exomes

AF:

0.0208

AC:

5222

AN:

251170

AF XY:

0.0229

show subpopulations

Gnomad AFR exome

AF:

0.00314

Gnomad AMR exome

AF:

0.0158

Gnomad ASJ exome

AF:

0.0641

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0114

Gnomad NFE exome

AF:

0.0196

Gnomad OTH exome

AF:

0.0271

GnomAD4 exome

AF:

0.0222

AC:

32408

AN:

1461778

Hom.:

475

Cov.:

AF XY:

0.0231

AC XY:

16799

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.00421

AC:

141

AN:

33480

American (AMR)

AF:

0.0162

AC:

726

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0627

AC:

1638

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39698

South Asian (SAS)

AF:

0.0430

AC:

3711

AN:

86256

European-Finnish (FIN)

AF:

0.0112

AC:

595

AN:

53332

Middle Eastern (MID)

AF:

0.0674

AC:

388

AN:

5758

European-Non Finnish (NFE)

AF:

0.0213

AC:

23728

AN:

1112000

Other (OTH)

AF:

0.0244

AC:

1476

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

1917

3834

5752

7669

9586

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

948

1896

2844

3792

4740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0163

AC:

2483

AN:

152150

Hom.:

Cov.:

AF XY:

0.0161

AC XY:

1196

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00446

AC:

185

AN:

41506

American (AMR)

AF:

0.0199

AC:

304

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0663

AC:

230

AN:

3470

East Asian (EAS)

AF:

0.000583

AC:

AN:

5144

South Asian (SAS)

AF:

0.0354

AC:

171

AN:

4824

European-Finnish (FIN)

AF:

0.0141

AC:

150

AN:

10604

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0201

AC:

1365

AN:

68004

Other (OTH)

AF:

0.0247

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

127

254

381

508

635

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0195

Hom.:

158

Bravo

AF:

0.0157

TwinsUK

AF:

0.0191

AC:

ALSPAC

AF:

0.0163

AC:

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.0233

AC:

200

ExAC

AF:

0.0202

AC:

2457

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0233

EpiControl

AF:

0.0234

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 14, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29578190, 22693617, 28609449, 14531790, 26040415) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Sep 20, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 23, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Kidney disorder

Benign:1

Mar 25, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial juvenile hyperuricemic nephropathy type 1

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.93

D;D;D;.

MetaRNN

Benign

0.0044

T;T;T;T

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

1.5

.;.;L;L

PhyloP100

2.0

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.3

N;.;N;.

REVEL

Uncertain

0.33

Sift

Uncertain

0.010

D;.;D;.

Sift4G

Uncertain

0.054

T;D;T;T

Polyphen

1.0

.;.;D;D

Vest4

0.42

MutPred

0.24

.;.;Loss of catalytic residue at V458 (P = 0.0124);Loss of catalytic residue at V458 (P = 0.0124);

MPC

0.52

ClinPred

0.025

GERP RS

5.3

Varity_R

0.64

gMVP

0.76

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over