16-20348994-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 5P and 5B. PM1PM5PP2BP4BS2

The NM_003361.4(UMOD):c.307G>A(p.Gly103Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,577,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. G103D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

UMOD
NM_003361.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.04

Publications

9 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: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_003361.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-20348994-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 12257.Status of the report is criteria_provided_single_submitter, 1 stars.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.28355813).

BS2

High AC in GnomAdExome4 at 24 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UMOD	NM_003361.4 link	c.307G>A	p.Gly103Ser	missense_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.307G>A	p.Gly103Ser	missense_variant	Exon 3 of 11	5	NM_003361.4	ENSP00000379442.5
UMOD	ENST00000396134.6 link	c.406G>A	p.Gly136Ser	missense_variant	Exon 4 of 12	2		ENSP00000379438.2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152248

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000528

AC:

AN:

189332

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.000200

GnomAD4 exome

AF:

0.0000168

AC:

AN:

1425188

Hom.:

Cov.:

AF XY:

0.0000184

AC XY:

AN XY:

705662

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32624

American (AMR)

AF:

0.00

AC:

AN:

39016

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25474

East Asian (EAS)

AF:

0.0000267

AC:

AN:

37494

South Asian (SAS)

AF:

0.0000489

AC:

AN:

81732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50304

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.0000165

AC:

AN:

1093722

Other (OTH)

AF:

0.0000169

AC:

AN:

59096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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:

0.00000657

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41476

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:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

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:

0.0000386

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Familial juvenile hyperuricemic nephropathy type 1

Uncertain:1

Jan 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;.;.;.;T;.;.;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.81

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

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.28

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

0.0

.;.;L;L;.;.;.;.

PhyloP100

3.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.53

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

REVEL

Uncertain

0.32

Sift

Benign

0.11

T;.;T;.;.;.;.;.

Sift4G

Uncertain

0.014

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

Vest4

0.22

ClinPred

0.93

GERP RS

4.5

Varity_R

0.035

gMVP

0.83

Mutation Taster

=33/67

disease causing

(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