16-20349071-C-T

Position:

• chr16-20349071-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_003361.4(UMOD):​c.230G>A​(p.Cys77Tyr) 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 (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: UMOD NM_003361.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.04

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 16-20349071-C-T is Pathogenic according to our data. Variant chr16-20349071-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12258.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UMOD	NM_003361.4	c.230G>A	p.Cys77Tyr	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.230G>A	p.Cys77Tyr	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: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial juvenile hyperuricemic nephropathy type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.84	.;.;.;.;D;.;.;.;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	.;.;H;H;.;.;.;.;.;.;.
MutationTaster	Benign	0.98	D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.8	D;D;D;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;.;.;D;D;.;.;D
Polyphen		1.0	.;.;D;D;.;.;.;.;.;.;.
Vest4		0.87
MutPred		0.98		.;.;Loss of disorder (P = 0.0391);Loss of disorder (P = 0.0391);.;Loss of disorder (P = 0.0391);.;.;Loss of disorder (P = 0.0391);Loss of disorder (P = 0.0391);Loss of disorder (P = 0.0391);
MVP		0.97
MPC		2.4
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.97
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: rs121917768; hg19: chr16-20360393;