NM_003361.4:c.1861+259A>G

Variant names:

• chr16-20335223-T-C
• rs9935075
• NM_003361.4:c.1861+259A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003361.4(UMOD):​c.1861+259A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0311 in 152,232 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.031 (150 hom., cov: 32)
• Consequence: UMOD NM_003361.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.157
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 16-20335223-T-C is Benign according to our data. Variant chr16-20335223-T-C is described in ClinVar as [Benign]. Clinvar id is 1289048.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.07 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UMOD	NM_003361.4	c.1861+259A>G		intron_variant	Intron 10 of 10	ENST00000396138.9	NP_003352.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UMOD	ENST00000396138.9	c.1861+259A>G		intron_variant	Intron 10 of 10	5	NM_003361.4	ENSP00000379442.5
UMOD	ENST00000396134.6	c.1960+259A>G		intron_variant	Intron 11 of 11	2		ENSP00000379438.2
UMOD	ENST00000570689.5	c.1861+259A>G		intron_variant	Intron 10 of 10	5		ENSP00000460548.1
UMOD	ENST00000570331.1	n.626+259A>G		intron_variant	Intron 5 of 5	5

Frequencies

GnomAD3 genomes AF: 0.0309 AC: 4695 AN: 152114 Hom.: 141 Cov.: 32

Gnomad AFR AF: 0.0714

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0227

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00636

Gnomad SAS AF: 0.0218

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0149

Gnomad OTH AF: 0.0335

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

GnomAD4 genome AF: 0.0311 AC: 4740 AN: 152232 Hom.: 150 Cov.: 32 AF XY: 0.0297 AC XY: 2210 AN XY: 74438

African (AFR) AF: 0.0721 AC: 2995 AN: 41526

American (AMR) AF: 0.0227 AC: 347 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3470

East Asian (EAS) AF: 0.00618 AC: 32 AN: 5176

South Asian (SAS) AF: 0.0216 AC: 104 AN: 4816

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10608

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0149 AC: 1014 AN: 68030

Other (OTH) AF: 0.0374 AC: 79 AN: 2110

Alfa AF: 0.0308 Hom.: 22

Bravo AF: 0.0352

Asia WGS AF: 0.0370 AC: 127 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 05, 2020

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	-0.93
CADD	Benign	1.5
DANN	Benign	0.73
PhyloP100		0.16
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: rs9935075; hg19: chr16-20346545;