chr16-20341541-G-C

Variant names:

• chr16-20341541-G-C
• rs9928757
• NM_003361.4:c.1332-205C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 publications found

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]

UMOD Gene-Disease associations (from GenCC):

• autosomal dominant medullary cystic kidney disease with or without hyperuricemia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• glomerulocystic kidney disease with hyperuricemia and isosthenuria

  Inheritance: AD Classification: DEFINITIVE Submitted by: Laboratory for Molecular Medicine
• familial juvenile hyperuricemic nephropathy type 1

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant medullary cystic kidney disease with hyperuricemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003361.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMOD	NM_003361.4	MANE Select	c.1332-205C>G		intron	N/A	NP_003352.2
	UMOD	NM_001378234.1		c.1473-205C>G		intron	N/A	NP_001365163.1
	UMOD	NM_001378235.1		c.1473-205C>G		intron	N/A	NP_001365164.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMOD	ENST00000396138.9	TSL:5 MANE Select	c.1332-205C>G		intron	N/A	ENSP00000379442.5
	UMOD	ENST00000396134.6	TSL:2	c.1431-205C>G		intron	N/A	ENSP00000379438.2
	UMOD	ENST00000570689.5	TSL:5	c.1332-205C>G		intron	N/A	ENSP00000460548.1

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

African (AFR) AF: 0.0544 AC: 2260 AN: 41550

American (AMR) AF: 0.179 AC: 2734 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 496 AN: 3466

East Asian (EAS) AF: 0.0112 AC: 58 AN: 5178

South Asian (SAS) AF: 0.147 AC: 708 AN: 4812

European-Finnish (FIN) AF: 0.259 AC: 2747 AN: 10590

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.205 AC: 13918 AN: 67998

Other (OTH) AF: 0.168 AC: 354 AN: 2112

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 17, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.1
DANN	Benign	0.65
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9928757; hg19: chr16-20352863;