chr16-20346076-G-A

Variant names:

• chr16-20346076-G-A
• rs4506906
• NM_003361.4:c.1182+50C>T

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.1182+50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 1,568,894 control chromosomes in the GnomAD database, including 274,825 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (19790 hom., cov: 33)
  • Exomes 𝑓: 0.58 (255035 hom.)
• Consequence: UMOD NM_003361.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.336
• 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=-0.77).
• BP6: Variant 16-20346076-G-A is Benign according to our data. Variant chr16-20346076-G-A is described in ClinVar as Benign. ClinVar VariationId is 1279719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UMOD	NM_003361.4	c.1182+50C>T		intron_variant	Intron 5 of 10	ENST00000396138.9	NP_003352.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UMOD	ENST00000396138.9	c.1182+50C>T		intron_variant	Intron 5 of 10	5	NM_003361.4	ENSP00000379442.5
UMOD	ENST00000396134.6	c.1281+50C>T		intron_variant	Intron 6 of 11	2		ENSP00000379438.2
UMOD	ENST00000570689.5	c.1182+50C>T		intron_variant	Intron 5 of 10	5		ENSP00000460548.1

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72404 AN: 151976 Hom.: 19788 Cov.: 33

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.588

Gnomad EAS AF: 0.0785

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.577

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.642

Gnomad OTH AF: 0.498

GnomAD2 exomes AF: 0.480 AC: 116820 AN: 243604 AF XY: 0.490

Gnomad AFR exome AF: 0.249

Gnomad AMR exome AF: 0.302

Gnomad ASJ exome AF: 0.594

Gnomad EAS exome AF: 0.0801

Gnomad FIN exome AF: 0.585

Gnomad NFE exome AF: 0.636

Gnomad OTH exome AF: 0.526

GnomAD4 exome AF: 0.583 AC: 826411 AN: 1416802 Hom.: 255035 Cov.: 24 AF XY: 0.578 AC XY: 407123 AN XY: 703946

African (AFR) AF: 0.251 AC: 8147 AN: 32516

American (AMR) AF: 0.313 AC: 13792 AN: 44120

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 15398 AN: 25708

East Asian (EAS) AF: 0.0580 AC: 2275 AN: 39230

South Asian (SAS) AF: 0.357 AC: 30330 AN: 84952

European-Finnish (FIN) AF: 0.589 AC: 31051 AN: 52744

Middle Eastern (MID) AF: 0.509 AC: 2193 AN: 4312

European-Non Finnish (NFE) AF: 0.644 AC: 691540 AN: 1074650

Other (OTH) AF: 0.541 AC: 31685 AN: 58570

GnomAD4 genome AF: 0.476 AC: 72417 AN: 152092 Hom.: 19790 Cov.: 33 AF XY: 0.463 AC XY: 34453 AN XY: 74362

African (AFR) AF: 0.263 AC: 10935 AN: 41500

American (AMR) AF: 0.396 AC: 6054 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 2039 AN: 3470

East Asian (EAS) AF: 0.0781 AC: 404 AN: 5174

South Asian (SAS) AF: 0.326 AC: 1567 AN: 4812

European-Finnish (FIN) AF: 0.577 AC: 6107 AN: 10588

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.642 AC: 43648 AN: 67958

Other (OTH) AF: 0.497 AC: 1049 AN: 2110

Alfa AF: 0.591 Hom.: 21666

Bravo AF: 0.450

Asia WGS AF: 0.206 AC: 718 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

- -

Jan 25, 2019

GeneDx

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	-0.77
CADD	Benign	2.6
DANN	Benign	0.79
PhyloP100		-0.34
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: rs4506906; hg19: chr16-20357398; COSMIC: COSV56775480; COSMIC: COSV56775480;