chr16-20341727-G-A

Variant names:

• chr16-20341727-G-A
• rs9928936
• NM_003361.4:c.1332-391C>T

Variant summary

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

The NM_003361.4(UMOD):​c.1332-391C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 152,114 control chromosomes in the GnomAD database, including 2,132 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 0.16 (2132 hom., cov: 33)
• Consequence: UMOD NM_003361.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0320
• Publications: 7 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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UMOD	NM_003361.4	c.1332-391C>T		intron_variant	Intron 6 of 10	ENST00000396138.9	NP_003352.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UMOD	ENST00000396138.9	c.1332-391C>T		intron_variant	Intron 6 of 10	5	NM_003361.4	ENSP00000379442.5
UMOD	ENST00000396134.6	c.1431-391C>T		intron_variant	Intron 7 of 11	2		ENSP00000379438.2
UMOD	ENST00000570689.5	c.1332-391C>T		intron_variant	Intron 6 of 10	5		ENSP00000460548.1
UMOD	ENST00000570331.1	n.97-391C>T		intron_variant	Intron 1 of 5	5

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24684 AN: 151996 Hom.: 2121 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0127

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.164

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

GnomAD4 genome AF: 0.162 AC: 24714 AN: 152114 Hom.: 2132 Cov.: 33 AF XY: 0.164 AC XY: 12185 AN XY: 74324

African (AFR) AF: 0.126 AC: 5238 AN: 41514

American (AMR) AF: 0.180 AC: 2750 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 513 AN: 3468

East Asian (EAS) AF: 0.0123 AC: 64 AN: 5184

South Asian (SAS) AF: 0.178 AC: 856 AN: 4814

European-Finnish (FIN) AF: 0.224 AC: 2358 AN: 10548

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12273 AN: 67982

Other (OTH) AF: 0.167 AC: 352 AN: 2112

Alfa AF: 0.166 Hom.: 3465

Bravo AF: 0.158

Asia WGS AF: 0.123 AC: 431 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.1
DANN	Benign	0.57
PhyloP100		0.032
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: rs9928936; hg19: chr16-20353049;