chr16-20333336-G-A

Position:

• chr16-20333336-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003361.4(UMOD):​c.1901C>T​(p.Thr634Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000992 in 1,461,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000099 (0 hom.)
• Consequence: UMOD NM_003361.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.464

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07257599).
• BS2: High AC in GnomAdExome4 at 145 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UMOD	NM_003361.4	c.1901C>T	p.Thr634Ile	missense_variant	11/11	ENST00000396138.9	NP_003352.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UMOD	ENST00000396138.9	c.1901C>T	p.Thr634Ile	missense_variant	11/11	5	NM_003361.4	ENSP00000379442	P2
UMOD	ENST00000396134.6	c.2000C>T	p.Thr667Ile	missense_variant	12/12	2		ENSP00000379438	A2
UMOD	ENST00000570689.5	c.1901C>T	p.Thr634Ile	missense_variant	11/11	5		ENSP00000460548	P2
UMOD	ENST00000570331.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249538 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 134922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000992 AC: 145 AN: 1461066 Hom.: 0 Cov.: 31 AF XY: 0.000100 AC XY: 73 AN XY: 726758

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: 0.000130

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000740 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant medullary cystic kidney disease with or without hyperuricemia Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Jan 12, 2018

This patient is heterozygous for a variant c.1901C>T p.(Thr634Ile) in the UMOD gene. To our knowledge, this variant has not been previously reported in the literature or any disease specific databases. The c.1901C>T p.(Thr634Ile) variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.001% (3 out of 244,382 alleles). In silico analysis (Alamut Visual v2.8.1) using SIFT, PolyPhen2 and MutationTaster all predict that this variant is likley to be benign. However, this analysis alone cannot be used to exclude pathogenicity. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines. -

Familial juvenile hyperuricemic nephropathy type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.88
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.50	T;T;T;.
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.073	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	.;.;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.25	N;.;N;.
REVEL	Benign	0.098
Sift	Benign	0.75	T;.;T;.
Sift4G	Benign	0.41	T;T;T;T
Polyphen		0.0	.;.;B;B
Vest4		0.17
MVP		0.42
MPC		0.11
ClinPred		0.034	T
GERP RS		1.2
Varity_R		0.043
gMVP		0.34

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: rs751927256; hg19: chr16-20344658;