rs9928757

Positions:

• chr16-20341541-G-C

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.1332-205C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 152,212 control chromosomes in the GnomAD database, including 2,285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.15 (2285 hom., cov: 32)
• Consequence: UMOD NM_003361.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.511

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=-0.84).
• BP6: Variant 16-20341541-G-C is Benign according to our data. Variant chr16-20341541-G-C is described in ClinVar as [Benign]. Clinvar id is 1229970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UMOD	NM_003361.4	c.1332-205C>G		intron_variant		ENST00000396138.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UMOD	ENST00000396138.9	c.1332-205C>G		intron_variant		5	NM_003361.4	P2
UMOD	ENST00000396134.6	c.1431-205C>G		intron_variant		2		A2
UMOD	ENST00000570689.5	c.1332-205C>G		intron_variant		5		P2
UMOD	ENST00000570331.1	n.97-205C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23570 AN: 152094 Hom.: 2283 Cov.: 32

Gnomad AFR AF: 0.0541

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.166

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.155 AC: 23583 AN: 152212 Hom.: 2285 Cov.: 32 AF XY: 0.156 AC XY: 11640 AN XY: 74416

Gnomad4 AFR AF: 0.0544

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.0112

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.259

Gnomad4 NFE AF: 0.205

Gnomad4 OTH AF: 0.168

Alfa AF: 0.174 Hom.: 326

Bravo AF: 0.144

Asia WGS AF: 0.0870 AC: 302 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.1
DANN	Benign	0.65

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: rs9928757; hg19: chr16-20352863;