16-20341296-C-A

Variant names:

• chr16-20341296-C-A
• rs55772253
• NM_003361.4:c.1372G>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_003361.4(UMOD):​c.1372G>T​(p.Val458Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,613,928 control chromosomes in the GnomAD database, including 509 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V458M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (34 hom., cov: 31)
  • Exomes 𝑓: 0.022 (475 hom.)
• Consequence: UMOD NM_003361.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.96
• Publications: 17 publications found

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: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant medullary cystic kidney disease with hyperuricemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.004376799).
• BP6: Variant 16-20341296-C-A is Benign according to our data. Variant chr16-20341296-C-A is described in ClinVar as Benign. ClinVar VariationId is 290985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0619 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMOD	NM_003361.4	MANE Select	c.1372G>T	p.Val458Leu	missense	Exon 7 of 11	NP_003352.2	P07911-1
	UMOD	NM_001378234.1		c.1513G>T	p.Val505Leu	missense	Exon 8 of 12	NP_001365163.1
	UMOD	NM_001378235.1		c.1513G>T	p.Val505Leu	missense	Exon 8 of 12	NP_001365164.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMOD	ENST00000396138.9	TSL:5 MANE Select	c.1372G>T	p.Val458Leu	missense	Exon 7 of 11	ENSP00000379442.5	P07911-1
	UMOD	ENST00000396134.6	TSL:2	c.1471G>T	p.Val491Leu	missense	Exon 8 of 12	ENSP00000379438.2	P07911-5
	UMOD	ENST00000863077.1		c.1534G>T	p.Val512Leu	missense	Exon 8 of 12	ENSP00000533136.1

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2487 AN: 152032 Hom.: 35 Cov.: 31

Gnomad AFR AF: 0.00447

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.0663

Gnomad EAS AF: 0.000582

Gnomad SAS AF: 0.0354

Gnomad FIN AF: 0.0141

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0254

GnomAD2 exomes AF: 0.0208 AC: 5222 AN: 251170 AF XY: 0.0229

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.0158

Gnomad ASJ exome AF: 0.0641

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.0196

Gnomad OTH exome AF: 0.0271

GnomAD4 exome AF: 0.0222 AC: 32408 AN: 1461778 Hom.: 475 Cov.: 35 AF XY: 0.0231 AC XY: 16799 AN XY: 727180

African (AFR) AF: 0.00421 AC: 141 AN: 33480

American (AMR) AF: 0.0162 AC: 726 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0627 AC: 1638 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.0430 AC: 3711 AN: 86256

European-Finnish (FIN) AF: 0.0112 AC: 595 AN: 53332

Middle Eastern (MID) AF: 0.0674 AC: 388 AN: 5758

European-Non Finnish (NFE) AF: 0.0213 AC: 23728 AN: 1112000

Other (OTH) AF: 0.0244 AC: 1476 AN: 60394

GnomAD4 genome AF: 0.0163 AC: 2483 AN: 152150 Hom.: 34 Cov.: 31 AF XY: 0.0161 AC XY: 1196 AN XY: 74390

African (AFR) AF: 0.00446 AC: 185 AN: 41506

American (AMR) AF: 0.0199 AC: 304 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0663 AC: 230 AN: 3470

East Asian (EAS) AF: 0.000583 AC: 3 AN: 5144

South Asian (SAS) AF: 0.0354 AC: 171 AN: 4824

European-Finnish (FIN) AF: 0.0141 AC: 150 AN: 10604

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0201 AC: 1365 AN: 68004

Other (OTH) AF: 0.0247 AC: 52 AN: 2108

Alfa AF: 0.0195 Hom.: 158

Bravo AF: 0.0157

TwinsUK AF: 0.0191 AC: 71

ALSPAC AF: 0.0163 AC: 63

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.0233 AC: 200

ExAC AF: 0.0202 AC: 2457

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.0233

EpiControl AF: 0.0234

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Familial juvenile hyperuricemic nephropathy type 1 (1)
-	-	1	Kidney disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0044	T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.5	L
PhyloP100		2.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.054	T
Polyphen		1.0	D
Vest4		0.42
MutPred		0.24		Loss of catalytic residue at V458 (P = 0.0124)
MPC		0.52
ClinPred		0.025	T
GERP RS		5.3
Varity_R		0.64
gMVP		0.76
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55772253; hg19: chr16-20352618; COSMIC: COSV100207997;