rs55772253

chr16-20341296-C-Achr16-20341296-C-Gchr16-20341296-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. 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 same amino acid change has been previously reported as Uncertain significancein 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:6
• Conservation: PhyloP100: 1.96

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• 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 id is 290985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-20341296-C-A is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UMOD	NM_003361.4	c.1372G>T	p.Val458Leu	missense_variant	7/11	ENST00000396138.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UMOD	ENST00000396138.9	c.1372G>T	p.Val458Leu	missense_variant	7/11	5	NM_003361.4	P2
UMOD	ENST00000396134.6	c.1471G>T	p.Val491Leu	missense_variant	8/12	2		A2
UMOD	ENST00000570689.5	c.1372G>T	p.Val458Leu	missense_variant	7/11	5		P2
UMOD	ENST00000570331.1	n.137G>T		non_coding_transcript_exon_variant	2/6	5

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

GnomAD3 exomes AF: 0.0208 AC: 5222 AN: 251170 Hom.: 105 AF XY: 0.0229 AC XY: 3111 AN XY: 135774

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 SAS exome AF: 0.0435

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

Gnomad4 AFR exome AF: 0.00421

Gnomad4 AMR exome AF: 0.0162

Gnomad4 ASJ exome AF: 0.0627

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0430

Gnomad4 FIN exome AF: 0.0112

Gnomad4 NFE exome AF: 0.0213

Gnomad4 OTH exome AF: 0.0244

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

Gnomad4 AFR AF: 0.00446

Gnomad4 AMR AF: 0.0199

Gnomad4 ASJ AF: 0.0663

Gnomad4 EAS AF: 0.000583

Gnomad4 SAS AF: 0.0354

Gnomad4 FIN AF: 0.0141

Gnomad4 NFE AF: 0.0201

Gnomad4 OTH AF: 0.0247

Alfa AF: 0.0199 Hom.: 74

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

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial juvenile hyperuricemic nephropathy type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2021	This variant is associated with the following publications: (PMID: 29578190, 22693617, 28609449, 14531790, 26040415) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 20, 2016

- -

Kidney disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

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;D;D;.
MetaRNN	Benign	0.0044	T;T;T;T
MetaSVM	Uncertain	0.35	D
MutationTaster	Benign	0.76	D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.3	N;.;N;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.010	D;.;D;.
Sift4G	Uncertain	0.054	T;D;T;T
Polyphen		1.0	.;.;D;D
Vest4		0.42
MutPred		0.24		.;.;Loss of catalytic residue at V458 (P = 0.0124);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

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

Publications

LitVar

Other links and lift over

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