16-20335223-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
UMOD	NM_003361.4	c.1861+259A>G		intron_variant		ENST00000396138.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UMOD	ENST00000396138.9	c.1861+259A>G		intron_variant		5	NM_003361.4	P2
UMOD	ENST00000396134.6	c.1960+259A>G		intron_variant		2		A2
UMOD	ENST00000570689.5	c.1861+259A>G		intron_variant		5		P2
UMOD	ENST00000570331.1	n.626+259A>G		intron_variant, non_coding_transcript_variant		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

Gnomad4 AFR AF: 0.0721

Gnomad4 AMR AF: 0.0227

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00618

Gnomad4 SAS AF: 0.0216

Gnomad4 FIN AF: 0.00471

Gnomad4 NFE AF: 0.0149

Gnomad4 OTH AF: 0.0374

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 05, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	1.5
Dann	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs9935075; hg19: chr16-20346545;