rs780462125

chr16-20348975-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP3_ModeratePP5

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).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_003361.4

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 id is 562322.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UMOD	NM_003361.4 linkuse as main transcript	c.326T>A	p.Val109Glu	missense_variant	3/11	ENST00000396138.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UMOD	ENST00000396138.9 linkuse as main transcript	c.326T>A	p.Val109Glu	missense_variant	3/11	5	NM_003361.4	P2	P07911-1

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

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183918

Hom.:

AF XY:

0.0000202

AC XY:

AN XY:

98798

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 SAS exome

AF:

0.0000403

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000268

Gnomad4 SAS exome

AF:

0.0000123

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000824

Gnomad4 OTH exome

AF:

0.0000509

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000833

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 12, 2022	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on UMOD protein function. ClinVar contains an entry for this variant (Variation ID: 562322). This missense change has been observed in individual(s) with autosomal dominant medullary cystic kidney disease (PMID: 23988501). This variant is present in population databases (rs780462125, gnomAD 0.004%). This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 109 of the UMOD protein (p.Val109Glu). Experimental studies have shown that this missense change affects UMOD function (PMID: 23988501). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

UMOD-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

This variant has been previously reported as a heterozygous change in patients with kidney disease (PMID: 23988501, 30586318, 33574344). Functional analysis showed that the c.326T>A (p.Val109Glu) variant alters the function of the UMOD protein (PMID: 23988501). The c.326T>A (p.Val109Glu) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/215296) and thus is presumed to be rare. The c.326T>A (p.Val109Glu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.326T>A (p.Val109Glu) variant is classified as Likely Pathogenic. -

Kidney disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.14

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.89

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

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.88

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

MetaSVM

Pathogenic

0.95

MutationTaster

Benign

0.99

D;D;D;D;D;D

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.3

N;.;N;.;.;.;.

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0

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

Vest4

0.66

MutPred

0.71

.;.;Gain of disorder (P = 0.0089);Gain of disorder (P = 0.0089);.;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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over