16-20348484-C-T

Position:

• chr16-20348484-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_003361.4(UMOD):​c.817G>A​(p.Val273Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,654 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: UMOD NM_003361.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.96

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a disulfide_bond (size 87) in uniprot entity UROM_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_003361.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UMOD	NM_003361.4	c.817G>A	p.Val273Ile	missense_variant	3/11	ENST00000396138.9	NP_003352.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UMOD	ENST00000396138.9	c.817G>A	p.Val273Ile	missense_variant	3/11	5	NM_003361.4	ENSP00000379442.5
UMOD	ENST00000396134.6	c.916G>A	p.Val306Ile	missense_variant	4/12	2		ENSP00000379438.2
UMOD	ENST00000570689.5	c.817G>A	p.Val273Ile	missense_variant	3/11	5		ENSP00000460548.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459654 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	0.14
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D;D;D;.
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	.;.;M;M
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.68	N;.;N;.
REVEL	Uncertain	0.52
Sift	Benign	0.053	T;.;T;.
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.56	.;.;P;P
Vest4		0.20
MutPred		0.86		.;.;Gain of catalytic residue at V273 (P = 0.1188);Gain of catalytic residue at V273 (P = 0.1188);
MVP		0.73
MPC		0.13
ClinPred		0.70	D
GERP RS		3.7
Varity_R		0.040
gMVP		0.40

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: rs121917774; hg19: chr16-20359806;