dbSNP rs780462125: UMOD:p.Val109Glu (chr16-20348975-A-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 10P and 4B. PS3PM1PP2PP3_ModeratePP5BS2

The NM_003361.4(UMOD):c.326T>A(p.Val109Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000108 in 1,573,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV004046134: Functional analysis showed that the c.326T>A (p.Val109Glu) variant alters the function of the UMOD protein (PMID:23988501).".

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000098 ( 0 hom. )

Consequence

UMOD
NM_003361.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 4.81

Publications

7 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: Unknown, AD 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_pathogenic. The variant received 6 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV004046134: Functional analysis showed that the c.326T>A (p.Val109Glu) variant alters the function of the UMOD protein (PMID: 23988501).

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_003361.4

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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.881

PP5

Variant 16-20348975-A-T is Pathogenic according to our data. Variant chr16-20348975-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 562322.

BS2

High AC in GnomAdExome4 at 14 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003361.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UMOD	NM_003361.4	MANE Select	c.326T>A	p.Val109Glu	missense	Exon 3 of 11	NP_003352.2	P07911-1
UMOD	NM_001378234.1		c.326T>A	p.Val109Glu	missense	Exon 3 of 12	NP_001365163.1
UMOD	NM_001378235.1		c.326T>A	p.Val109Glu	missense	Exon 3 of 12	NP_001365164.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UMOD	ENST00000396138.9	TSL:5 MANE Select	c.326T>A	p.Val109Glu	missense	Exon 3 of 11	ENSP00000379442.5	P07911-1
UMOD	ENST00000396134.6	TSL:2	c.425T>A	p.Val142Glu	missense	Exon 4 of 12	ENSP00000379438.2	P07911-5
UMOD	ENST00000863077.1		c.488T>A	p.Val163Glu	missense	Exon 4 of 12	ENSP00000533136.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183918

AF XY:

0.0000202

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000130

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000985

AC:

AN:

1421496

Hom.:

Cov.:

AF XY:

0.0000171

AC XY:

AN XY:

703496

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32576

American (AMR)

AF:

0.00

AC:

AN:

38810

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25394

East Asian (EAS)

AF:

0.0000268

AC:

AN:

37362

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81320

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49638

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00000824

AC:

AN:

1091762

Other (OTH)

AF:

0.0000509

AC:

AN:

58914

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000833

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Kidney disorder (1)

UMOD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.88

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.2

PhyloP100

4.8

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.3

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.66

MutPred

0.71

Gain of disorder (P = 0.0089)

MVP

0.89

MPC

1.8

ClinPred

0.89

GERP RS

5.5

Varity_R

0.62

gMVP

0.98

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over