Genetic Variant UMOD:p.Asn128Ser (chr16-20348918-T-C) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_003361.4(UMOD):c.383A>G(p.Asn128Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N128D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

UMOD
NM_003361.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.37

Publications

8 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_003361.4

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 16-20348918-T-C is Pathogenic according to our data. Variant chr16-20348918-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 12260.Status of the report is no_assertion_criteria_provided, 0 stars.

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
UMOD	NM_003361.4	MANE Select	c.383A>G	p.Asn128Ser	missense	Exon 3 of 11	NP_003352.2
UMOD	NM_001378234.1		c.383A>G	p.Asn128Ser	missense	Exon 3 of 12	NP_001365163.1
UMOD	NM_001378235.1		c.383A>G	p.Asn128Ser	missense	Exon 3 of 12	NP_001365164.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
UMOD	ENST00000396138.9	TSL:5 MANE Select	c.383A>G	p.Asn128Ser	missense	Exon 3 of 11	ENSP00000379442.5
UMOD	ENST00000396134.6	TSL:2	c.482A>G	p.Asn161Ser	missense	Exon 4 of 12	ENSP00000379438.2
UMOD	ENST00000570689.5	TSL:5	c.383A>G	p.Asn128Ser	missense	Exon 3 of 11	ENSP00000460548.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1413926

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699148

African (AFR)

AF:

0.00

AC:

AN:

32392

American (AMR)

AF:

0.00

AC:

AN:

37972

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25310

East Asian (EAS)

AF:

0.00

AC:

AN:

37026

South Asian (SAS)

AF:

0.00

AC:

AN:

80606

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48648

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1087720

Other (OTH)

AF:

0.00

AC:

AN:

58540

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Familial juvenile hyperuricemic nephropathy type 1

Pathogenic:1

Mar 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

PhyloP100

4.4

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.60

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.71

MutPred

0.97

Gain of glycosylation at N128 (P = 0.1281)

MVP

0.90

MPC

1.7

ClinPred

0.96

GERP RS

5.5

Varity_R

0.67

gMVP

0.90

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over