UMOD p.Cys106Phe

Variant names:

• chr16-20348984-C-A
• rs398123697
• NM_003361.4:c.317G>T
• UMOD p.Cys106Phe

Your query was ambiguous. Multiple possible variants found:

• chr16-20348984-C-A
• chr16-20348983-GC-AA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 14P and 4B. PS3 PM1 PM5 PP2 PP3_Strong PP5 BS2

The NM_003361.4(UMOD):​c.317G>T​(p.Cys106Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000445 in 1,574,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001810844: Published functional studies suggest abnormal protein folding and aggregation (PMID:32926855)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C106Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: UMOD NM_003361.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1 O:1
• Conservation: PhyloP100: 4.13
• Publications: 11 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: Unknown, AD 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: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001810844: Published functional studies suggest abnormal protein folding and aggregation (PMID: 32926855); SCV002242196: Experimental studies have shown that this missense change affects UMOD function (PMID: 32926855).; SCV001478436: A functional study using a mouse homolog of the UMOD p.Cys106Phe variant suggests that misfolded and aggregated uromodulin engages the kidney's immune system, resulting in auto-antibody and immune complex formation.; SCV004105465: Functional studies using a mouse model showed that this variant results in autoantibodies against aggregated misfolded protein with immune complex formation and kidney fibrosis (Plotkin et al. 2020. PubMed ID: 32926855).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_003361.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-20348984-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 807521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 69 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 0.99836 (below the threshold of 3.09). Trascript score misZ: 0.48416 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant medullary cystic kidney disease with hyperuricemia, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, familial juvenile hyperuricemic nephropathy type 1, glomerulocystic kidney disease with hyperuricemia and isosthenuria.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 16-20348984-C-A is Pathogenic according to our data. Variant chr16-20348984-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94129.
• BS2: High AC in GnomAdExome4 at 6 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003361.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMOD	NM_003361.4	MANE Select	c.317G>T	p.Cys106Phe	missense	Exon 3 of 11	NP_003352.2	P07911-1
	UMOD	NM_001378234.1		c.317G>T	p.Cys106Phe	missense	Exon 3 of 12	NP_001365163.1
	UMOD	NM_001378235.1		c.317G>T	p.Cys106Phe	missense	Exon 3 of 12	NP_001365164.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMOD	ENST00000396138.9	TSL:5 MANE Select	c.317G>T	p.Cys106Phe	missense	Exon 3 of 11	ENSP00000379442.5	P07911-1
	UMOD	ENST00000396134.6	TSL:2	c.416G>T	p.Cys139Phe	missense	Exon 4 of 12	ENSP00000379438.2	P07911-5
	UMOD	ENST00000863077.1		c.479G>T	p.Cys160Phe	missense	Exon 4 of 12	ENSP00000533136.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152280 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 184308 AF XY: 0.0000101

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000260

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000422 AC: 6 AN: 1421900 Hom.: 0 Cov.: 39 AF XY: 0.00000426 AC XY: 3 AN XY: 703700

African (AFR) AF: 0.00 AC: 0 AN: 32558

American (AMR) AF: 0.00 AC: 0 AN: 38744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25424

East Asian (EAS) AF: 0.00 AC: 0 AN: 37350

South Asian (SAS) AF: 0.00 AC: 0 AN: 81398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000366 AC: 4 AN: 1091942

Other (OTH) AF: 0.0000339 AC: 2 AN: 58930

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74398

African (AFR) AF: 0.00 AC: 0 AN: 41486

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	1	-	not provided (5)
3	-	-	Familial juvenile hyperuricemic nephropathy type 1 (4)
1	-	-	UMOD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		4.1
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs398123697;

hg19: chr16-20360306;