rs78691203

Positions:

• chr16-20348461-G-A
• chr16-20348461-G-C
• chr16-20348461-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003361.4(UMOD):​c.840C>T​(p.Pro280=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00362 in 1,613,124 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (61 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (69 hom.)
• Consequence: UMOD NM_003361.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.75

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 16-20348461-G-A is Benign according to our data. Variant chr16-20348461-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 196362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UMOD	NM_003361.4	c.840C>T	p.Pro280=	synonymous_variant	3/11	ENST00000396138.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UMOD	ENST00000396138.9	c.840C>T	p.Pro280=	synonymous_variant	3/11	5	NM_003361.4	P2
UMOD	ENST00000396134.6	c.939C>T	p.Pro313=	synonymous_variant	4/12	2		A2
UMOD	ENST00000570689.5	c.840C>T	p.Pro280=	synonymous_variant	3/11	5		P2

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2612 AN: 152224 Hom.: 61 Cov.: 33

Gnomad AFR AF: 0.0567

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00824

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00537 AC: 1326 AN: 246698 Hom.: 29 AF XY: 0.00430 AC XY: 576 AN XY: 134108

Gnomad AFR exome AF: 0.0597

Gnomad AMR exome AF: 0.00322

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000594

Gnomad OTH exome AF: 0.00414

GnomAD4 exome AF: 0.00221 AC: 3226 AN: 1460782 Hom.: 69 Cov.: 35 AF XY: 0.00203 AC XY: 1473 AN XY: 726710

Gnomad4 AFR exome AF: 0.0585

Gnomad4 AMR exome AF: 0.00349

Gnomad4 ASJ exome AF: 0.0183

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000250

Gnomad4 OTH exome AF: 0.00538

GnomAD4 genome AF: 0.0172 AC: 2620 AN: 152342 Hom.: 61 Cov.: 33 AF XY: 0.0171 AC XY: 1272 AN XY: 74508

Gnomad4 AFR AF: 0.0567

Gnomad4 AMR AF: 0.00823

Gnomad4 ASJ AF: 0.0207

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00708 Hom.: 14

Bravo AF: 0.0200

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.000653

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial juvenile hyperuricemic nephropathy type 1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 27, 2014

- -

Kidney disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.4
DANN	Benign	0.89

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: rs78691203; hg19: chr16-20359783;