rs111699931

Variant names:

• chr16-20333210-G-A
• rs111699931
• NM_003361.4:c.*104C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-20333210-G-A
• chr16-20333210-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 5 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=-0.81).
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3638 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UMOD	NM_003361.4	c.*104C>T		3_prime_UTR_variant	Exon 11 of 11	ENST00000396138.9	NP_003352.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UMOD	ENST00000396138.9	c.*104C>T		3_prime_UTR_variant	Exon 11 of 11	5	NM_003361.4	ENSP00000379442.5
UMOD	ENST00000396134.6	c.*104C>T		3_prime_UTR_variant	Exon 12 of 12	2		ENSP00000379438.2
UMOD	ENST00000570689.5	c.*104C>T		3_prime_UTR_variant	Exon 11 of 11	5		ENSP00000460548.1
UMOD	ENST00000570331.1	n.*129C>T		downstream_gene_variant		5

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

African (AFR) AF: 0.00514 AC: 127 AN: 24726

American (AMR) AF: 0.0121 AC: 443 AN: 36554

Ashkenazi Jewish (ASJ) AF: 0.0220 AC: 505 AN: 22912

East Asian (EAS) AF: 0.0000289 AC: 1 AN: 34654

South Asian (SAS) AF: 0.0153 AC: 1107 AN: 72480

European-Finnish (FIN) AF: 0.0479 AC: 2372 AN: 49544

Middle Eastern (MID) AF: 0.0173 AC: 60 AN: 3466

European-Non Finnish (NFE) AF: 0.0358 AC: 27133 AN: 756950

Other (OTH) AF: 0.0256 AC: 1184 AN: 46324

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

African (AFR) AF: 0.00654 AC: 272 AN: 41574

American (AMR) AF: 0.0150 AC: 229 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4826

European-Finnish (FIN) AF: 0.0508 AC: 538 AN: 10600

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0352 AC: 2397 AN: 68034

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.0183 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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 07, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial juvenile hyperuricemic nephropathy type 1 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.7
DANN	Benign	0.40
PhyloP100		1.2
Mutation Taster		=99/1	polymorphism

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: rs111699931; hg19: chr16-20344532;