chr16-20348557-G-A

Variant names:

• chr16-20348557-G-A
• rs886043751
• NM_003361.4:c.744C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_003361.4(UMOD):​c.744C>T​(p.Cys248Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,446,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.437
• Publications: 12 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP7: Synonymous conserved (PhyloP=-0.437 with no splicing effect.

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.744C>T	p.Cys248Cys	synonymous	Exon 3 of 11	NP_003352.2
	UMOD	NM_001378234.1		c.744C>T	p.Cys248Cys	synonymous	Exon 3 of 12	NP_001365163.1
	UMOD	NM_001378235.1		c.744C>T	p.Cys248Cys	synonymous	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.744C>T	p.Cys248Cys	synonymous	Exon 3 of 11	ENSP00000379442.5
	UMOD	ENST00000396134.6	TSL:2	c.843C>T	p.Cys281Cys	synonymous	Exon 4 of 12	ENSP00000379438.2
	UMOD	ENST00000570689.5	TSL:5	c.744C>T	p.Cys248Cys	synonymous	Exon 3 of 11	ENSP00000460548.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1446238 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 719218

African (AFR) AF: 0.00 AC: 0 AN: 33340

American (AMR) AF: 0.00 AC: 0 AN: 43480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39312

South Asian (SAS) AF: 0.00 AC: 0 AN: 84966

European-Finnish (FIN) AF: 0.0000223 AC: 1 AN: 44800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108696

Other (OTH) AF: 0.00 AC: 0 AN: 59980

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.3
DANN	Benign	0.95
PhyloP100		-0.44

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: rs886043751; hg19: chr16-20359879;