4-39446966-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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 made for transcript

Verdict is Benign. Variant got -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 id 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

GnomAD3 exomes

AF:

0.0360

AC:

8589

AN:

238528

Hom.:

219

AF XY:

0.0371

AC XY:

4869

AN XY:

131132

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 SAS exome

AF:

0.0267

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

Gnomad4 AFR exome

AF:

0.00831

Gnomad4 AMR exome

AF:

0.0127

Gnomad4 ASJ exome

AF:

0.0281

Gnomad4 EAS exome

AF:

0.00106

Gnomad4 SAS exome

AF:

0.0264

Gnomad4 FIN exome

AF:

0.0525

Gnomad4 NFE exome

AF:

0.0560

Gnomad4 OTH exome

AF:

0.0445

GnomAD4 genome

AF:

0.0345

AC:

5256

AN:

152332

Hom.:

145

Cov.:

AF XY:

0.0337

AC XY:

2513

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00943

Gnomad4 AMR

AF:

0.0157

Gnomad4 ASJ

AF:

0.0228

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.0199

Gnomad4 FIN

AF:

0.0543

Gnomad4 NFE

AF:

0.0549

Gnomad4 OTH

AF:

0.0365

Alfa

AF:

0.0434

Hom.:

132

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over