chr16-20341296-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2BS2

The NM_003361.4(UMOD):c.1372G>A(p.Val458Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V458L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

UMOD
NM_003361.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

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: Likely_benign. The variant received -3 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.

BS2

High AC in GnomAdExome4 at 11 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UMOD	NM_003361.4 link	c.1372G>A	p.Val458Met	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>A	p.Val458Met	missense_variant	Exon 7 of 11	5	NM_003361.4	ENSP00000379442.5	P07911-1X6RBG4
UMOD	ENST00000396134.6 link	c.1471G>A	p.Val491Met	missense_variant	Exon 8 of 12	2		ENSP00000379438.2	P07911-5
UMOD	ENST00000570689.5 link	c.1372G>A	p.Val458Met	missense_variant	Exon 7 of 11	5		ENSP00000460548.1	P07911-1
UMOD	ENST00000570331.1 link	n.137G>A		non_coding_transcript_exon_variant	Exon 2 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251170

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112000

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000131

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41506

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

158

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial juvenile hyperuricemic nephropathy type 1

Uncertain:1

Feb 14, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense c.1372G>A (p.Val458Met) variant in UMOD gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Val458Met variant has allele frequency 0.002% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has not been reported to the ClinVar database. The amino acid change p.Val458Met in UMOD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Val at position 458 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -

not provided

Uncertain:1

Apr 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in individuals affected with UMOD-related conditions. This variant is present in population databases (rs55772253, gnomAD 0.02%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 458 of the UMOD protein (p.Val458Met). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.95

D;D;D;.

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.69

D;D;D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Uncertain

2.3

.;.;M;M

PhyloP100

2.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.3

N;.;N;.

REVEL

Uncertain

0.51

Sift

Uncertain

0.0030

D;.;D;.

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0

.;.;D;D

Vest4

0.49

MutPred

0.51

.;.;Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.79

MPC

0.52

ClinPred

0.73

GERP RS

5.3

Varity_R

0.64

gMVP

0.74

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over