16-20333210-G-A

Position:

• chr16-20333210-G-A

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.*104C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0305 in 1,199,912 control chromosomes in the GnomAD database, including 673 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (72 hom., cov: 32)
  • Exomes 𝑓: 0.031 (601 hom.)
• Consequence: UMOD NM_003361.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.17

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 (BayesDel_noAF=-0.81).
• BP6: Variant 16-20333210-G-A is Benign according to our data. Variant chr16-20333210-G-A is described in ClinVar as [Benign]. Clinvar id is 318279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-20333210-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0239 (3638/152302) while in subpopulation NFE AF= 0.0352 (2397/68034). AF 95% confidence interval is 0.0341. There are 72 homozygotes in gnomad4. There are 1798 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3638 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UMOD	NM_003361.4	c.*104C>T		3_prime_UTR_variant	11/11	ENST00000396138.9	NP_003352.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UMOD	ENST00000396138.9	c.*104C>T		3_prime_UTR_variant	11/11	5	NM_003361.4	ENSP00000379442	P2
UMOD	ENST00000396134.6	c.*104C>T		3_prime_UTR_variant	12/12	2		ENSP00000379438	A2
UMOD	ENST00000570689.5	c.*104C>T		3_prime_UTR_variant	11/11	5		ENSP00000460548	P2

Frequencies

GnomAD3 genomes AF: 0.0239 AC: 3638 AN: 152184 Hom.: 72 Cov.: 32

Gnomad AFR AF: 0.00656

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0150

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0508

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0352

Gnomad OTH AF: 0.0172

GnomAD4 exome AF: 0.0314 AC: 32932 AN: 1047610 Hom.: 601 Cov.: 14 AF XY: 0.0307 AC XY: 16373 AN XY: 533026

Gnomad4 AFR exome AF: 0.00514

Gnomad4 AMR exome AF: 0.0121

Gnomad4 ASJ exome AF: 0.0220

Gnomad4 EAS exome AF: 0.0000289

Gnomad4 SAS exome AF: 0.0153

Gnomad4 FIN exome AF: 0.0479

Gnomad4 NFE exome AF: 0.0358

Gnomad4 OTH exome AF: 0.0256

GnomAD4 genome AF: 0.0239 AC: 3638 AN: 152302 Hom.: 72 Cov.: 32 AF XY: 0.0241 AC XY: 1798 AN XY: 74456

Gnomad4 AFR AF: 0.00654

Gnomad4 AMR AF: 0.0150

Gnomad4 ASJ AF: 0.0259

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.0508

Gnomad4 NFE AF: 0.0352

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0271 Hom.: 11

Bravo AF: 0.0203

Asia WGS AF: 0.00404 AC: 14 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial juvenile hyperuricemic nephropathy type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.7
DANN	Benign	0.40

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: rs111699931; hg19: chr16-20344532;