13-33054001-T-G

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.1054T>G(p.Phe352Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,612,748 control chromosomes in the GnomAD database, including 20,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 1938 hom., cov: 32)

Exomes 𝑓: 0.15 ( 18471 hom. )

Consequence

KL
NM_004795.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.89

Publications

139 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=0.0017518401).

BP6

Variant 13-33054001-T-G is Benign according to our data. Variant chr13-33054001-T-G is described in ClinVar as Benign. ClinVar VariationId is 311690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KL	NM_004795.4 link	c.1054T>G	p.Phe352Val	missense_variant	Exon 2 of 5	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3 link	c.133T>G	p.Phe45Val	missense_variant	Exon 2 of 5		XP_006719958.1
KL	XM_047430775.1 link	c.1054T>G	p.Phe352Val	missense_variant	Exon 2 of 4		XP_047286731.1
KL	XM_047430776.1 link	c.1054T>G	p.Phe352Val	missense_variant	Exon 2 of 4		XP_047286732.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4 link	c.1054T>G	p.Phe352Val	missense_variant	Exon 2 of 5	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1 link	n.1062T>G		non_coding_transcript_exon_variant	Exon 2 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.156

AC:

23680

AN:

151982

Hom.:

1937

Cov.:

show subpopulations

Gnomad AFR

AF:

0.183

Gnomad AMI

AF:

0.106

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.216

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.192

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.155

Gnomad OTH

AF:

0.149

GnomAD2 exomes

AF:

0.141

AC:

35479

AN:

251294

AF XY:

0.146

show subpopulations

Gnomad AFR exome

AF:

0.181

Gnomad AMR exome

AF:

0.0735

Gnomad ASJ exome

AF:

0.206

Gnomad EAS exome

AF:

0.00114

Gnomad FIN exome

AF:

0.200

Gnomad NFE exome

AF:

0.152

Gnomad OTH exome

AF:

0.147

GnomAD4 exome

AF:

0.154

AC:

225219

AN:

1460648

Hom.:

18471

Cov.:

AF XY:

0.155

AC XY:

112556

AN XY:

726572

show subpopulations

African (AFR)

AF:

0.178

AC:

5959

AN:

33452

American (AMR)

AF:

0.0769

AC:

3440

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.208

AC:

5439

AN:

26130

East Asian (EAS)

AF:

0.000857

AC:

AN:

39684

South Asian (SAS)

AF:

0.174

AC:

14999

AN:

86230

European-Finnish (FIN)

AF:

0.198

AC:

10566

AN:

53396

Middle Eastern (MID)

AF:

0.163

AC:

938

AN:

5766

European-Non Finnish (NFE)

AF:

0.157

AC:

173893

AN:

1110922

Other (OTH)

AF:

0.165

AC:

9951

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

9278

18557

27835

37114

46392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6200

12400

18600

24800

31000

<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:

0.156

AC:

23693

AN:

152100

Hom.:

1938

Cov.:

AF XY:

0.157

AC XY:

11658

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.183

AC:

7577

AN:

41476

American (AMR)

AF:

0.103

AC:

1571

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.216

AC:

749

AN:

3472

East Asian (EAS)

AF:

0.000965

AC:

AN:

5180

South Asian (SAS)

AF:

0.162

AC:

778

AN:

4806

European-Finnish (FIN)

AF:

0.192

AC:

2033

AN:

10580

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.155

AC:

10526

AN:

67972

Other (OTH)

AF:

0.147

AC:

312

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1025

2050

3075

4100

5125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

250

500

750

1000

1250

<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:

0.148

Hom.:

7764

Bravo

AF:

0.148

TwinsUK

AF:

0.161

AC:

597

ALSPAC

AF:

0.169

AC:

650

ESP6500AA

AF:

0.185

AC:

816

ESP6500EA

AF:

0.164

AC:

1411

ExAC

AF:

0.143

AC:

17372

Asia WGS

AF:

0.0750

AC:

264

AN:

3478

EpiCase

AF:

0.154

EpiControl

AF:

0.155

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19421891, 29247834, 15677572, 11792841, 19802015, 24217253, 21376714, 21093413)

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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:2

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 06, 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

Uncertain

0.49

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.2

MutationAssessor

Benign

2.0

PhyloP100

7.9

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-7.0

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Vest4

0.33

ClinPred

0.022

GERP RS

5.9

Varity_R

0.96

gMVP

0.95

Mutation Taster

=15/85

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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