rs55772253

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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 (★★).

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

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:

UMOD (HGNC:):

UMOD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

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 id is 290985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-20341296-C-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
UMOD	NM_003361.4 linkuse as main transcript	c.1372G>T	p.Val458Leu	missense_variant	7/11	ENST00000396138.9	NP_003352.2	P07911-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
UMOD	ENST00000396138.9 linkuse as main transcript	c.1372G>T	p.Val458Leu	missense_variant	7/11	5	NM_003361.4	ENSP00000379442.5	P07911-1X6RBG4
UMOD	ENST00000396134.6 linkuse as main transcript	c.1471G>T	p.Val491Leu	missense_variant	8/12	2		ENSP00000379438.2	P07911-5
UMOD	ENST00000570689.5 linkuse as main transcript	c.1372G>T	p.Val458Leu	missense_variant	7/11	5		ENSP00000460548.1	P07911-1
UMOD	ENST00000570331.1 linkuse as main transcript	n.137G>T		non_coding_transcript_exon_variant	2/6	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

GnomAD3 exomes

AF:

0.0208

AC:

5222

AN:

251170

Hom.:

105

AF XY:

0.0229

AC XY:

3111

AN XY:

135774

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 SAS exome

AF:

0.0435

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

Gnomad4 AFR exome

AF:

0.00421

Gnomad4 AMR exome

AF:

0.0162

Gnomad4 ASJ exome

AF:

0.0627

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0430

Gnomad4 FIN exome

AF:

0.0112

Gnomad4 NFE exome

AF:

0.0213

Gnomad4 OTH exome

AF:

0.0244

GnomAD4 genome

AF:

0.0163

AC:

2483

AN:

152150

Hom.:

Cov.:

AF XY:

0.0161

AC XY:

1196

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00446

Gnomad4 AMR

AF:

0.0199

Gnomad4 ASJ

AF:

0.0663

Gnomad4 EAS

AF:

0.000583

Gnomad4 SAS

AF:

0.0354

Gnomad4 FIN

AF:

0.0141

Gnomad4 NFE

AF:

0.0201

Gnomad4 OTH

AF:

0.0247

Alfa

AF:

0.0199

Hom.:

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2021	This variant is associated with the following publications: (PMID: 29578190, 22693617, 28609449, 14531790, 26040415) -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2017	- -

Kidney disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 25, 2022

- -

Familial juvenile hyperuricemic nephropathy type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

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

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

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

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