Genetic Variant UMOD:p.Gly295Gly (chr16-20348311-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003361.4(UMOD):c.885G>A(p.Gly295Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,614,024 control chromosomes in the GnomAD database, including 25,159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G295G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.15 ( 1916 hom., cov: 33)

Exomes 𝑓: 0.17 ( 23243 hom. )

Consequence

UMOD
NM_003361.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.49

Publications

15 publications found

Variant links:

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

UMOD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 16-20348311-C-T is Benign according to our data. Variant chr16-20348311-C-T is described in ClinVar as Benign. ClinVar VariationId is 94132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.49 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
UMOD	NM_003361.4	MANE Select	c.885G>A	p.Gly295Gly	synonymous	Exon 4 of 11	NP_003352.2
UMOD	NM_001378234.1		c.885G>A	p.Gly295Gly	synonymous	Exon 4 of 12	NP_001365163.1
UMOD	NM_001378235.1		c.885G>A	p.Gly295Gly	synonymous	Exon 4 of 12	NP_001365164.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
UMOD	ENST00000396138.9	TSL:5 MANE Select	c.885G>A	p.Gly295Gly	synonymous	Exon 4 of 11	ENSP00000379442.5
UMOD	ENST00000396134.6	TSL:2	c.984G>A	p.Gly328Gly	synonymous	Exon 5 of 12	ENSP00000379438.2
UMOD	ENST00000863077.1		c.1047G>A	p.Gly349Gly	synonymous	Exon 5 of 12	ENSP00000533136.1

Frequencies

GnomAD3 genomes

AF:

0.149

AC:

22644

AN:

152168

Hom.:

1912

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0797

Gnomad AMI

AF:

0.276

Gnomad AMR

AF:

0.171

Gnomad ASJ

AF:

0.148

Gnomad EAS

AF:

0.0121

Gnomad SAS

AF:

0.167

Gnomad FIN

AF:

0.226

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.181

Gnomad OTH

AF:

0.156

GnomAD2 exomes

AF:

0.159

AC:

40022

AN:

251440

AF XY:

0.164

show subpopulations

Gnomad AFR exome

AF:

0.0749

Gnomad AMR exome

AF:

0.145

Gnomad ASJ exome

AF:

0.144

Gnomad EAS exome

AF:

0.0117

Gnomad FIN exome

AF:

0.222

Gnomad NFE exome

AF:

0.181

Gnomad OTH exome

AF:

0.179

GnomAD4 exome

AF:

0.174

AC:

254267

AN:

1461738

Hom.:

23243

Cov.:

AF XY:

0.175

AC XY:

126913

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.0835

AC:

2794

AN:

33480

American (AMR)

AF:

0.151

AC:

6733

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.143

AC:

3731

AN:

26136

East Asian (EAS)

AF:

0.00562

AC:

223

AN:

39700

South Asian (SAS)

AF:

0.187

AC:

16147

AN:

86254

European-Finnish (FIN)

AF:

0.224

AC:

11940

AN:

53388

Middle Eastern (MID)

AF:

0.195

AC:

1127

AN:

5768

European-Non Finnish (NFE)

AF:

0.181

AC:

201613

AN:

1111894

Other (OTH)

AF:

0.165

AC:

9959

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

13966

27932

41898

55864

69830

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7012

14024

21036

28048

35060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.149

AC:

22648

AN:

152286

Hom.:

1916

Cov.:

AF XY:

0.151

AC XY:

11206

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0798

AC:

3320

AN:

41578

American (AMR)

AF:

0.171

AC:

2616

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.148

AC:

512

AN:

3470

East Asian (EAS)

AF:

0.0118

AC:

AN:

5190

South Asian (SAS)

AF:

0.166

AC:

799

AN:

4816

European-Finnish (FIN)

AF:

0.226

AC:

2391

AN:

10602

Middle Eastern (MID)

AF:

0.190

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.181

AC:

12308

AN:

68008

Other (OTH)

AF:

0.158

AC:

333

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

990

1981

2971

3962

4952

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

240

480

720

960

1200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.158

Hom.:

3798

Bravo

AF:

0.141

Asia WGS

AF:

0.0990

AC:

348

AN:

3478

EpiCase

AF:

0.182

EpiControl

AF:

0.186

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Familial juvenile hyperuricemic nephropathy type 1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

4.6

(source)

DANN

Benign

0.92

PhyloP100

-1.5

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over