16-20348557-G-C

Position:

• chr16-20348557-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_003361.4(UMOD):​c.744C>G​(p.Cys248Trp) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: UMOD NM_003361.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: -0.437

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a disulfide_bond (size 38) in uniprot entity UROM_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_003361.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 16-20348557-G-C is Pathogenic according to our data. Variant chr16-20348557-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 287876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UMOD	NM_003361.4	c.744C>G	p.Cys248Trp	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.744C>G	p.Cys248Trp	missense_variant	3/11	5	NM_003361.4	ENSP00000379442	P2
UMOD	ENST00000396134.6	c.843C>G	p.Cys281Trp	missense_variant	4/12	2		ENSP00000379438	A2
UMOD	ENST00000570689.5	c.744C>G	p.Cys248Trp	missense_variant	3/11	5		ENSP00000460548	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 02, 2021	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects UMOD function (PMID: 23988501). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 287876). This variant is also known as C849G. This missense change has been observed in individuals with UMOD-related conditions (PMID: 14531790, 17245395, 23988501). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 248 of the UMOD protein (p.Cys248Trp). -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 19, 2016	- -

UMOD-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 12, 2024

The UMOD c.744C>G variant is predicted to result in the amino acid substitution p.Cys248Trp. This variant has reported in several individuals in families with uromodulin-associated kidney disease (Wolf et al. 2003. PubMed ID: 14531790; Wolf et al. 2007. PubMed ID: 17245395; family F2, Liu et al. 2013. PubMed ID: 23988501; ID: F9, Gong et al. 2021. PubMed ID: 33574344). Immunofluorescence studies demonstrate that expression of this variant affects uromodulin intracellular trafficking (Liu et al. 2013. PubMed ID: 23988501). This variant has not been reported in a large population database, indicating this variant is rare. Additionally, a different missense change impacting the same amino acid (p.Cys248Ser) has been reported in members of a family with uromodulin-associated kidney disease (family F6, Zaucke et al. 2010. PubMed ID: 20172860). Taken together, the p.Cys248Trp variant is interpreted as pathogenic. -

Familial juvenile hyperuricemic nephropathy type 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

Possible association with Later onset of ESRD -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	19
DANN	Uncertain	0.99
Eigen	Benign	0.031
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.86	D;D;D;.
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	.;.;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.8	D;D;D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;.;D;D
Vest4		0.59
MutPred		0.88		.;.;Gain of MoRF binding (P = 0.0305);Gain of MoRF binding (P = 0.0305);
MVP		0.77
MPC		2.2
ClinPred		1.0	D
GERP RS		-4.2
Varity_R		0.93
gMVP		1.0

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: rs886043751; hg19: chr16-20359879;