16-20348484-C-G

Position:

• chr16-20348484-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_003361.4(UMOD):​c.817G>C​(p.Val273Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: UMOD NM_003361.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.96

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a disulfide_bond (size 87) in uniprot entity UROM_HUMAN there are 14 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, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UMOD	NM_003361.4	c.817G>C	p.Val273Leu	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.817G>C	p.Val273Leu	missense_variant	3/11	5	NM_003361.4	ENSP00000379442.5
UMOD	ENST00000396134.6	c.916G>C	p.Val306Leu	missense_variant	4/12	2		ENSP00000379438.2
UMOD	ENST00000570689.5	c.817G>C	p.Val273Leu	missense_variant	3/11	5		ENSP00000460548.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;.
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	.;.;M;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.1	N;.;N;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D;.;D;.
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.97	.;.;D;D
Vest4		0.51
MutPred		0.82		.;.;Loss of catalytic residue at T277 (P = 0.3072);Loss of catalytic residue at T277 (P = 0.3072);
MVP		0.96
MPC		0.35
ClinPred		0.97	D
GERP RS		3.7
Varity_R		0.15
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs121917774; hg19: chr16-20359806;