16-20333321-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003361.4(UMOD):c.1916T>C(p.Phe639Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000402 in 1,613,160 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (4 hom.)
• Consequence: UMOD NM_003361.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.170

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=0.0066948533).
• BP6: Variant 16-20333321-A-G is Benign according to our data. Variant chr16-20333321-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 318282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000282 (43/152250) while in subpopulation SAS AF= 0.00332 (16/4818). AF 95% confidence interval is 0.00208. There are 1 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UMOD	NM_003361.4	c.1916T>C	p.Phe639Ser	missense_variant	11/11	ENST00000396138.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UMOD	ENST00000396138.9	c.1916T>C	p.Phe639Ser	missense_variant	11/11	5	NM_003361.4	P2
UMOD	ENST00000396134.6	c.2015T>C	p.Phe672Ser	missense_variant	12/12	2		A2
UMOD	ENST00000570689.5	c.1916T>C	p.Phe639Ser	missense_variant	11/11	5		P2
UMOD	ENST00000570331.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152132 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000705 AC: 176 AN: 249646 Hom.: 1 AF XY: 0.000911 AC XY: 123 AN XY: 134962

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00297

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000390

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000415 AC: 606 AN: 1460910 Hom.: 4 Cov.: 31 AF XY: 0.000561 AC XY: 408 AN XY: 726660

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000381

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00317

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000175

Gnomad4 OTH exome AF: 0.000829

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152250 Hom.: 1 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74436

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000408 Hom.: 0

Bravo AF: 0.000215

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000733 AC: 89

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000534

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 08, 2018

- -

Familial juvenile hyperuricemic nephropathy type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	12
Dann	Benign	0.82
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.0041	N
LIST_S2	Benign	0.35	T;T;T;.
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.0067	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.2	N;.;N;.
REVEL	Benign	0.14
Sift	Benign	0.11	T;.;T;.
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.0	.;.;B;B
Vest4		0.054
MVP		0.41
MPC		0.18
ClinPred		0.013	T
GERP RS		2.0
Varity_R		0.089
gMVP		0.27

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: rs145165861; hg19: chr16-20344643;