NM_003361.4:c.307G>A

Variant names:

• chr16-20348994-C-T
• rs28934584
• NM_003361.4:c.307G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 5P and 5B. PM1 PM5 PP2 BP4 BS2

The NM_003361.4(UMOD):​c.307G>A​(p.Gly103Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,577,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G103D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: UMOD NM_003361.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.04
• Publications: 9 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: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_003361.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-20348994-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 12257.Status of the report is criteria_provided_single_submitter, 1 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 or without hyperuricemia, familial juvenile hyperuricemic nephropathy type 1, glomerulocystic kidney disease with hyperuricemia and isosthenuria, autosomal dominant medullary cystic kidney disease with hyperuricemia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.28355813).
• BS2: High AC in GnomAdExome4 at 24 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMOD	NM_003361.4	MANE Select	c.307G>A	p.Gly103Ser	missense	Exon 3 of 11	NP_003352.2
	UMOD	NM_001378234.1		c.307G>A	p.Gly103Ser	missense	Exon 3 of 12	NP_001365163.1
	UMOD	NM_001378235.1		c.307G>A	p.Gly103Ser	missense	Exon 3 of 12	NP_001365164.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UMOD	ENST00000396138.9	TSL:5 MANE Select	c.307G>A	p.Gly103Ser	missense	Exon 3 of 11	ENSP00000379442.5
	UMOD	ENST00000396134.6	TSL:2	c.406G>A	p.Gly136Ser	missense	Exon 4 of 12	ENSP00000379438.2
	UMOD	ENST00000570689.5	TSL:5	c.307G>A	p.Gly103Ser	missense	Exon 3 of 11	ENSP00000460548.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152248 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: 0.00000528 AC: 1 AN: 189332 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.000200

GnomAD4 exome AF: 0.0000168 AC: 24 AN: 1425188 Hom.: 0 Cov.: 39 AF XY: 0.0000184 AC XY: 13 AN XY: 705662

African (AFR) AF: 0.00 AC: 0 AN: 32624

American (AMR) AF: 0.00 AC: 0 AN: 39016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25474

East Asian (EAS) AF: 0.0000267 AC: 1 AN: 37494

South Asian (SAS) AF: 0.0000489 AC: 4 AN: 81732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.0000165 AC: 18 AN: 1093722

Other (OTH) AF: 0.0000169 AC: 1 AN: 59096

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152248 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74388

African (AFR) AF: 0.00 AC: 0 AN: 41476

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

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

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial juvenile hyperuricemic nephropathy type 1 Uncertain:1

Jan 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.0
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.53	N
REVEL	Uncertain	0.32
Sift	Benign	0.11	T
Sift4G	Uncertain	0.014	D
Polyphen		0.57	P
Vest4		0.22
MVP		0.54
MPC		1.5
ClinPred		0.93	D
GERP RS		4.5
Varity_R		0.035
gMVP		0.83
Mutation Taster		=33/67	disease causing

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: rs28934584; hg19: chr16-20360316;