chr16-20350628-C-T

Variant names:

• chr16-20350628-C-T
• rs36060036
• NM_003361.4:c.88+22G>A

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.88+22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,613,248 control chromosomes in the GnomAD database, including 20,422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1514 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18908 hom.)
• Consequence: UMOD NM_003361.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.458
• Publications: 9 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=-0.95).
• BP6: Variant 16-20350628-C-T is Benign according to our data. Variant chr16-20350628-C-T is described in ClinVar as Benign. ClinVar VariationId is 1226888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UMOD	NM_003361.4	c.88+22G>A		intron_variant	Intron 2 of 10	ENST00000396138.9	NP_003352.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UMOD	ENST00000396138.9	c.88+22G>A		intron_variant	Intron 2 of 10	5	NM_003361.4	ENSP00000379442.5
UMOD	ENST00000396134.6	c.88+22G>A		intron_variant	Intron 2 of 11	2		ENSP00000379438.2

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18745 AN: 152088 Hom.: 1514 Cov.: 32

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.00540

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.129

GnomAD2 exomes AF: 0.139 AC: 34711 AN: 249662 AF XY: 0.143

Gnomad AFR exome AF: 0.0243

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.00757

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.156 AC: 228156 AN: 1461042 Hom.: 18908 Cov.: 32 AF XY: 0.156 AC XY: 113384 AN XY: 726788

African (AFR) AF: 0.0256 AC: 858 AN: 33452

American (AMR) AF: 0.137 AC: 6116 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 3411 AN: 26118

East Asian (EAS) AF: 0.00335 AC: 133 AN: 39692

South Asian (SAS) AF: 0.140 AC: 12064 AN: 86166

European-Finnish (FIN) AF: 0.219 AC: 11664 AN: 53356

Middle Eastern (MID) AF: 0.142 AC: 821 AN: 5768

European-Non Finnish (NFE) AF: 0.166 AC: 184347 AN: 1111472

Other (OTH) AF: 0.145 AC: 8742 AN: 60362

GnomAD4 genome AF: 0.123 AC: 18734 AN: 152206 Hom.: 1514 Cov.: 32 AF XY: 0.126 AC XY: 9342 AN XY: 74408

African (AFR) AF: 0.0295 AC: 1226 AN: 41540

American (AMR) AF: 0.154 AC: 2351 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 469 AN: 3472

East Asian (EAS) AF: 0.00522 AC: 27 AN: 5176

South Asian (SAS) AF: 0.126 AC: 608 AN: 4828

European-Finnish (FIN) AF: 0.222 AC: 2348 AN: 10582

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.165 AC: 11222 AN: 67996

Other (OTH) AF: 0.128 AC: 270 AN: 2114

Alfa AF: 0.136 Hom.: 328

Bravo AF: 0.113

Asia WGS AF: 0.0710 AC: 248 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 17, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.82
DANN	Benign	0.46
PhyloP100		-0.46
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: rs36060036; hg19: chr16-20361950;