4-39446966-C-T

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.2240C>T(p.Ala747Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0477 in 1,606,872 control chromosomes in the GnomAD database, including 2,171 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 145 hom., cov: 33)

Exomes 𝑓: 0.049 ( 2026 hom. )

Consequence

KLB
NM_175737.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.86

Publications

18 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=0.0045126975).

BP6

Variant 4-39446966-C-T is Benign according to our data. Variant chr4-39446966-C-T is described in ClinVar as Benign. ClinVar VariationId is 1599207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLB	NM_175737.4 link	c.2240C>T	p.Ala747Val	missense_variant	Exon 4 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.2240C>T	p.Ala747Val	missense_variant	Exon 4 of 5	1	NM_175737.4	ENSP00000257408.4		Q86Z14

Frequencies

GnomAD3 genomes

AF:

0.0345

AC:

5256

AN:

152214

Hom.:

145

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00945

Gnomad AMI

AF:

0.0548

Gnomad AMR

AF:

0.0158

Gnomad ASJ

AF:

0.0228

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.0199

Gnomad FIN

AF:

0.0543

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0549

Gnomad OTH

AF:

0.0368

GnomAD2 exomes

AF:

0.0360

AC:

8589

AN:

238528

AF XY:

0.0371

show subpopulations

Gnomad AFR exome

AF:

0.00889

Gnomad AMR exome

AF:

0.0116

Gnomad ASJ exome

AF:

0.0273

Gnomad EAS exome

AF:

0.000281

Gnomad FIN exome

AF:

0.0548

Gnomad NFE exome

AF:

0.0539

Gnomad OTH exome

AF:

0.0324

GnomAD4 exome

AF:

0.0490

AC:

71316

AN:

1454540

Hom.:

2026

Cov.:

AF XY:

0.0487

AC XY:

35293

AN XY:

724002

show subpopulations

African (AFR)

AF:

0.00831

AC:

278

AN:

33470

American (AMR)

AF:

0.0127

AC:

569

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.0281

AC:

733

AN:

26062

East Asian (EAS)

AF:

0.00106

AC:

AN:

39688

South Asian (SAS)

AF:

0.0264

AC:

2277

AN:

86172

European-Finnish (FIN)

AF:

0.0525

AC:

2456

AN:

46822

Middle Eastern (MID)

AF:

0.0144

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0560

AC:

62196

AN:

1111586

Other (OTH)

AF:

0.0445

AC:

2682

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

4265

8529

12794

17058

21323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2214

4428

6642

8856

11070

<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:

0.0345

AC:

5256

AN:

152332

Hom.:

145

Cov.:

AF XY:

0.0337

AC XY:

2513

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00943

AC:

392

AN:

41586

American (AMR)

AF:

0.0157

AC:

241

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

AN:

3470

East Asian (EAS)

AF:

0.00116

AC:

AN:

5178

South Asian (SAS)

AF:

0.0199

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0543

AC:

576

AN:

10616

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0549

AC:

3733

AN:

68022

Other (OTH)

AF:

0.0365

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

256

513

769

1026

1282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0426

Hom.:

217

Bravo

AF:

0.0306

TwinsUK

AF:

0.0418

AC:

155

ALSPAC

AF:

0.0522

AC:

201

ESP6500AA

AF:

0.00570

AC:

ESP6500EA

AF:

0.0520

AC:

445

ExAC

AF:

0.0369

AC:

4450

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0474

EpiControl

AF:

0.0472

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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

Feb 21, 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

0.13

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

Eigen

Benign

0.11

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.40

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PhyloP100

1.9

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.2

REVEL

Benign

0.082

Sift

Benign

0.39

Sift4G

Benign

0.99

Polyphen

0.96

Vest4

0.063

MPC

0.79

ClinPred

0.040

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.53

gMVP

0.91

Mutation Taster

=87/13

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