Genetic Variant NM_003361.4:c.1860G>T (chr16-20335483-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003361.4(UMOD):c.1860G>T(p.Leu620Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

UMOD
NM_003361.4 missense, splice_region

Scores

Splicing: ADA: 0.00005611

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.109

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15142441).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UMOD	NM_003361.4 link	c.1860G>T	p.Leu620Phe	missense_variant, splice_region_variant	Exon 10 of 11	ENST00000396138.9	NP_003352.2	P07911-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UMOD	ENST00000396138.9 link	c.1860G>T	p.Leu620Phe	missense_variant, splice_region_variant	Exon 10 of 11	5	NM_003361.4	ENSP00000379442.5	P07911-1X6RBG4
UMOD	ENST00000396134.6 link	c.1959G>T	p.Leu653Phe	missense_variant, splice_region_variant	Exon 11 of 12	2		ENSP00000379438.2	P07911-5
UMOD	ENST00000570689.5 link	c.1860G>T	p.Leu620Phe	missense_variant, splice_region_variant	Exon 10 of 11	5		ENSP00000460548.1	P07911-1
UMOD	ENST00000570331.1 link	n.625G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 6	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727200

show subpopulations

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.72

T;T;T;.

M_CAP

Benign

0.032

MetaRNN

Benign

0.15

T;T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.4

.;.;M;M

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.6

N;.;N;.

REVEL

Benign

0.21

Sift

Uncertain

0.015

D;.;D;.

Sift4G

Uncertain

0.044

D;D;D;D

Polyphen

0.74

.;.;P;P

Vest4

0.21

MutPred

0.38

.;.;Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);

MVP

0.48

MPC

0.11

ClinPred

0.59

GERP RS

-1.0

Varity_R

0.12

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000056

dbscSNV1_RF

Benign

0.036

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over