rs3752472

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004795.4(KL):c.1540C>T(p.Pro514Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0093 in 1,614,160 control chromosomes in the GnomAD database, including 692 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 92 hom., cov: 32)

Exomes 𝑓: 0.0086 ( 600 hom. )

Consequence

KL
NM_004795.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 5.73

Publications

28 publications found

Variant links:

Genes affected

KL (HGNC:6344): (klotho) This gene encodes a type-I membrane protein that is related to beta-glucosidases. Reduced production of this protein has been observed in patients with chronic renal failure (CRF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. Also, mutations within this protein have been associated with ageing and bone loss. [provided by RefSeq, Jul 2008]

KL Gene-Disease associations (from GenCC):

tumoral calcinosis, hyperphosphatemic, familial, 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
tumoral calcinosis, hyperphosphatemic, familial, 3
Inheritance: AR, Unknown Classification: LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

KL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018047988).

BP6

Variant 13-33055256-C-T is Benign according to our data. Variant chr13-33055256-C-T is described in ClinVar as Benign. ClinVar VariationId is 311695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0762 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KL	NM_004795.4 link	c.1540C>T	p.Pro514Ser	missense_variant	Exon 3 of 5	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3 link	c.619C>T	p.Pro207Ser	missense_variant	Exon 3 of 5		XP_006719958.1
KL	XM_047430775.1 link	c.1540C>T	p.Pro514Ser	missense_variant	Exon 3 of 4		XP_047286731.1
KL	XM_047430776.1 link	c.1540C>T	p.Pro514Ser	missense_variant	Exon 3 of 4		XP_047286732.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4 link	c.1540C>T	p.Pro514Ser	missense_variant	Exon 3 of 5	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1 link	n.1548C>T		non_coding_transcript_exon_variant	Exon 3 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.0159

AC:

2416

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0148

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0670

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.0823

Gnomad SAS

AF:

0.0197

Gnomad FIN

AF:

0.0116

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.0293

AC:

7356

AN:

251440

AF XY:

0.0243

show subpopulations

Gnomad AFR exome

AF:

0.0146

Gnomad AMR exome

AF:

0.129

Gnomad ASJ exome

AF:

0.0100

Gnomad EAS exome

AF:

0.0851

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.00138

Gnomad OTH exome

AF:

0.0197

GnomAD4 exome

AF:

0.00861

AC:

12584

AN:

1461866

Hom.:

600

Cov.:

AF XY:

0.00826

AC XY:

6010

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0134

AC:

447

AN:

33478

American (AMR)

AF:

0.117

AC:

5251

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00979

AC:

256

AN:

26136

East Asian (EAS)

AF:

0.0847

AC:

3361

AN:

39700

South Asian (SAS)

AF:

0.0148

AC:

1278

AN:

86256

European-Finnish (FIN)

AF:

0.0107

AC:

569

AN:

53410

Middle Eastern (MID)

AF:

0.00329

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000606

AC:

674

AN:

1112000

Other (OTH)

AF:

0.0121

AC:

729

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

774

1548

2323

3097

3871

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

352

528

704

880

<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:

0.0159

AC:

2426

AN:

152294

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

1364

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0148

AC:

617

AN:

41566

American (AMR)

AF:

0.0674

AC:

1031

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00865

AC:

AN:

3470

East Asian (EAS)

AF:

0.0827

AC:

428

AN:

5178

South Asian (SAS)

AF:

0.0193

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0116

AC:

123

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00110

AC:

AN:

68024

Other (OTH)

AF:

0.0137

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

111

222

334

445

556

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00825

Hom.:

176

Bravo

AF:

0.0212

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00999

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.0259

AC:

3140

Asia WGS

AF:

0.0530

AC:

185

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Tumoral calcinosis, hyperphosphatemic, familial, 3

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

5.7

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.19

Sift

Benign

0.21

Sift4G

Uncertain

0.051

Polyphen

0.40

Vest4

0.22

MPC

0.14

ClinPred

0.017

GERP RS

6.0

Varity_R

0.30

gMVP

0.81

Mutation Taster

=88/12

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over