16-20344843-A-G

Variant names:

• chr16-20344843-A-G
• rs11647727
• NM_003361.4:c.1183-671T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003361.4(UMOD):​c.1183-671T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.682 in 151,978 control chromosomes in the GnomAD database, including 36,133 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.68 (36133 hom., cov: 31)
• Consequence: UMOD NM_003361.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.153
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.747 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.1183-671T>C		intron	N/A	NP_003352.2
	UMOD	NM_001378234.1		c.1183-671T>C		intron	N/A	NP_001365163.1
	UMOD	NM_001378235.1		c.1183-671T>C		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.1183-671T>C		intron	N/A	ENSP00000379442.5
	UMOD	ENST00000396134.6	TSL:2	c.1282-671T>C		intron	N/A	ENSP00000379438.2
	UMOD	ENST00000570689.5	TSL:5	c.1183-671T>C		intron	N/A	ENSP00000460548.1

Frequencies

GnomAD3 genomes AF: 0.682 AC: 103592 AN: 151860 Hom.: 36115 Cov.: 31

Gnomad AFR AF: 0.680

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.726

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.664

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.752

Gnomad OTH AF: 0.696

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

GnomAD4 genome AF: 0.682 AC: 103643 AN: 151978 Hom.: 36133 Cov.: 31 AF XY: 0.668 AC XY: 49590 AN XY: 74278

African (AFR) AF: 0.680 AC: 28155 AN: 41434

American (AMR) AF: 0.577 AC: 8800 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.726 AC: 2519 AN: 3468

East Asian (EAS) AF: 0.299 AC: 1539 AN: 5152

South Asian (SAS) AF: 0.461 AC: 2217 AN: 4810

European-Finnish (FIN) AF: 0.664 AC: 7005 AN: 10550

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.752 AC: 51122 AN: 67984

Other (OTH) AF: 0.693 AC: 1463 AN: 2112

Alfa AF: 0.725 Hom.: 126184

Bravo AF: 0.674

Asia WGS AF: 0.413 AC: 1439 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.7
DANN	Benign	0.54
PhyloP100		-0.15
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: rs11647727; hg19: chr16-20356165;