rs28934584

Positions:

• chr16-20348994-C-A
• chr16-20348994-C-G
• chr16-20348994-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_003361.4(UMOD):​c.307G>T​(p.Gly103Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: UMOD NM_003361.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.04

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 16-20348994-C-A is Pathogenic according to our data. Variant chr16-20348994-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12257.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UMOD	NM_003361.4	c.307G>T	p.Gly103Cys	missense_variant	3/11	ENST00000396138.9	NP_003352.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UMOD	ENST00000396138.9	c.307G>T	p.Gly103Cys	missense_variant	3/11	5	NM_003361.4	ENSP00000379442	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial juvenile hyperuricemic nephropathy type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2002

- -

UMOD-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 29, 2023

The UMOD c.307G>T variant is predicted to result in the amino acid substitution p.Gly103Cys. This variant was reported to segregate with medullary cystic kidney disease 2 in three affected and five unaffected individuals from a single family (Family 3, Hart et al 2002. PubMed ID: 12471200), and has also been reported in one unrelated individual with autosomal dominant tubulointerstitial kidney disease (Table S1, Olinger et al. 2020. PubMed ID: 32450155). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	.;.;.;.;T;.;.;.
Eigen	Benign	0.055
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.85	T;D;D;.;T;T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	2.9	.;.;M;M;.;.;.;.
MutationTaster	Benign	3.3e-9	A;A;A;A;A;A
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N;.;N;.;.;.;.;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.021	D;.;D;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;.;.;D;D
Polyphen		0.99	.;.;D;D;.;.;.;.
Vest4		0.38
MutPred		0.87		.;.;Gain of catalytic residue at P102 (P = 0.0118);Gain of catalytic residue at P102 (P = 0.0118);.;Gain of catalytic residue at P102 (P = 0.0118);.;.;
MVP		0.81
MPC		1.9
ClinPred		0.84	D
GERP RS		4.5
Varity_R		0.12
gMVP		0.96

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

Other links and lift over

dbSNP: rs28934584; hg19: chr16-20360316;