rs4975017

Variant names:

Variant summary

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

The NM_175737.4(KLB):c.3058C>A(p.Gln1020Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,613,676 control chromosomes in the GnomAD database, including 89,808 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 7057 hom., cov: 33)

Exomes 𝑓: 0.33 ( 82751 hom. )

Consequence

KLB
NM_175737.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.30

Publications

46 publications found

Variant links:

Genes affected

KLB (HGNC:15527): (klotho beta) Enables fibroblast growth factor binding activity and fibroblast growth factor receptor binding activity. Predicted to be involved in fibroblast growth factor receptor signaling pathway. Predicted to act upstream of or within positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway and positive regulation of cell population proliferation. Predicted to be located in plasma membrane. Predicted to be active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

KLB 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=0.002471596).

BP6

Variant 4-39448609-C-A is Benign according to our data. Variant chr4-39448609-C-A is described in ClinVar as Benign. ClinVar VariationId is 1287276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLB	NM_175737.4 link	c.3058C>A	p.Gln1020Lys	missense_variant	Exon 5 of 5	ENST00000257408.5	NP_783864.1	Q86Z14B4DYH5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLB	ENST00000257408.5 link	c.3058C>A	p.Gln1020Lys	missense_variant	Exon 5 of 5	1	NM_175737.4	ENSP00000257408.4		Q86Z14

Frequencies

GnomAD3 genomes

AF:

0.290

AC:

44061

AN:

151936

Hom.:

7049

Cov.:

show subpopulations

Gnomad AFR

AF:

0.150

Gnomad AMI

AF:

0.388

Gnomad AMR

AF:

0.368

Gnomad ASJ

AF:

0.238

Gnomad EAS

AF:

0.395

Gnomad SAS

AF:

0.444

Gnomad FIN

AF:

0.371

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.328

Gnomad OTH

AF:

0.270

GnomAD2 exomes

AF:

0.350

AC:

87813

AN:

251232

AF XY:

0.352

show subpopulations

Gnomad AFR exome

AF:

0.140

Gnomad AMR exome

AF:

0.455

Gnomad ASJ exome

AF:

0.228

Gnomad EAS exome

AF:

0.389

Gnomad FIN exome

AF:

0.369

Gnomad NFE exome

AF:

0.326

Gnomad OTH exome

AF:

0.327

GnomAD4 exome

AF:

0.332

AC:

485216

AN:

1461622

Hom.:

82751

Cov.:

AF XY:

0.335

AC XY:

243371

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.137

AC:

4603

AN:

33480

American (AMR)

AF:

0.440

AC:

19655

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.236

AC:

6173

AN:

26132

East Asian (EAS)

AF:

0.390

AC:

15489

AN:

39686

South Asian (SAS)

AF:

0.427

AC:

36816

AN:

86246

European-Finnish (FIN)

AF:

0.372

AC:

19868

AN:

53378

Middle Eastern (MID)

AF:

0.212

AC:

1221

AN:

5768

European-Non Finnish (NFE)

AF:

0.327

AC:

363156

AN:

1111826

Other (OTH)

AF:

0.302

AC:

18235

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

18237

36474

54712

72949

91186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11806

23612

35418

47224

59030

<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:

0.290

AC:

44087

AN:

152054

Hom.:

7057

Cov.:

AF XY:

0.297

AC XY:

22090

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.150

AC:

6213

AN:

41482

American (AMR)

AF:

0.369

AC:

5627

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.238

AC:

828

AN:

3472

East Asian (EAS)

AF:

0.394

AC:

2042

AN:

5178

South Asian (SAS)

AF:

0.444

AC:

2139

AN:

4818

European-Finnish (FIN)

AF:

0.371

AC:

3919

AN:

10550

Middle Eastern (MID)

AF:

0.235

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.328

AC:

22320

AN:

67976

Other (OTH)

AF:

0.274

AC:

578

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1589

3178

4768

6357

7946

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

464

928

1392

1856

2320

<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:

0.319

Hom.:

26028

Bravo

AF:

0.280

TwinsUK

AF:

0.330

AC:

1223

ALSPAC

AF:

0.334

AC:

1286

ESP6500AA

AF:

0.155

AC:

684

ESP6500EA

AF:

0.325

AC:

2792

ExAC

AF:

0.343

AC:

41621

Asia WGS

AF:

0.435

AC:

1513

AN:

3478

EpiCase

AF:

0.317

EpiControl

AF:

0.315

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

KLB-related disorder

Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.12

DEOGEN2

Benign

0.025

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.95

PhyloP100

1.3

PrimateAI

Benign

0.25

PROVEAN

Benign

0.26

REVEL

Benign

0.068

Sift

Benign

1.0

Sift4G

Benign

0.88

Polyphen

0.049

Vest4

0.086

MPC

0.0056

ClinPred

0.0078

GERP RS

2.8

Varity_R

0.12

gMVP

0.27

Mutation Taster

=97/3

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