NM_003361.4:c.522C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003361.4(UMOD):c.522C>T(p.Cys174Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.709 in 1,543,230 control chromosomes in the GnomAD database, including 396,875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.68 ( 35967 hom., cov: 35)

Exomes 𝑓: 0.71 ( 360908 hom. )

Consequence

UMOD
NM_003361.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.93

Publications

19 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 16-20348779-G-A is Benign according to our data. Variant chr16-20348779-G-A is described in ClinVar as Benign. ClinVar VariationId is 94130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.93 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UMOD	NM_003361.4 link	c.522C>T	p.Cys174Cys	synonymous_variant	Exon 3 of 11	ENST00000396138.9	NP_003352.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UMOD	ENST00000396138.9 link	c.522C>T	p.Cys174Cys	synonymous_variant	Exon 3 of 11	5	NM_003361.4	ENSP00000379442.5
UMOD	ENST00000396134.6 link	c.621C>T	p.Cys207Cys	synonymous_variant	Exon 4 of 12	2		ENSP00000379438.2

Frequencies

GnomAD3 genomes

AF:

0.680

AC:

103430

AN:

152068

Hom.:

35948

Cov.:

show subpopulations

Gnomad AFR

AF:

0.678

Gnomad AMI

AF:

0.681

Gnomad AMR

AF:

0.573

Gnomad ASJ

AF:

0.725

Gnomad EAS

AF:

0.308

Gnomad SAS

AF:

0.459

Gnomad FIN

AF:

0.663

Gnomad MID

AF:

0.690

Gnomad NFE

AF:

0.749

Gnomad OTH

AF:

0.696

GnomAD2 exomes

AF:

0.615

AC:

88092

AN:

143242

AF XY:

0.616

show subpopulations

Gnomad AFR exome

AF:

0.669

Gnomad AMR exome

AF:

0.488

Gnomad ASJ exome

AF:

0.722

Gnomad EAS exome

AF:

0.306

Gnomad FIN exome

AF:

0.677

Gnomad NFE exome

AF:

0.747

Gnomad OTH exome

AF:

0.651

GnomAD4 exome

AF:

0.713

AC:

991150

AN:

1391042

Hom.:

360908

Cov.:

100

AF XY:

0.707

AC XY:

484861

AN XY:

686050

show subpopulations

African (AFR)

AF:

0.668

AC:

21069

AN:

31528

American (AMR)

AF:

0.497

AC:

17717

AN:

35628

Ashkenazi Jewish (ASJ)

AF:

0.727

AC:

18250

AN:

25112

East Asian (EAS)

AF:

0.303

AC:

10801

AN:

35668

South Asian (SAS)

AF:

0.483

AC:

38217

AN:

79122

European-Finnish (FIN)

AF:

0.678

AC:

29089

AN:

42902

Middle Eastern (MID)

AF:

0.660

AC:

3552

AN:

5382

European-Non Finnish (NFE)

AF:

0.754

AC:

812721

AN:

1077878

Other (OTH)

AF:

0.687

AC:

39734

AN:

57822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

19787

39575

59362

79150

98937

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19786

39572

59358

79144

98930

<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:

0.680

AC:

103484

AN:

152188

Hom.:

35967

Cov.:

AF XY:

0.666

AC XY:

49581

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.678

AC:

28139

AN:

41528

American (AMR)

AF:

0.572

AC:

8750

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.725

AC:

2515

AN:

3470

East Asian (EAS)

AF:

0.308

AC:

1588

AN:

5150

South Asian (SAS)

AF:

0.461

AC:

2224

AN:

4826

European-Finnish (FIN)

AF:

0.663

AC:

7041

AN:

10614

Middle Eastern (MID)

AF:

0.680

AC:

200

AN:

294

European-Non Finnish (NFE)

AF:

0.749

AC:

50940

AN:

67982

Other (OTH)

AF:

0.693

AC:

1466

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1709

3418

5127

6836

8545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

804

1608

2412

3216

4020

<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:

0.731

Hom.:

14370

Bravo

AF:

0.671

Asia WGS

AF:

0.414

AC:

1441

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

May 19, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 07, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Familial juvenile hyperuricemic nephropathy type 1

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

9.1

(source)

DANN

Benign

0.93

PhyloP100

2.9

Mutation Taster

=56/44

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over