Variant chr4-39446909-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_175737.4(KLB):c.2183G>A(p.Arg728Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 1,605,394 control chromosomes in the GnomAD database, including 27,915 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 same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.16 ( 2245 hom., cov: 33)

Exomes 𝑓: 0.19 ( 25670 hom. )

Consequence

KLB
NM_175737.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.426

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=0.0029337704).

BP6

Variant 4-39446909-G-A is Benign according to our data. Variant chr4-39446909-G-A is described in ClinVar as [Benign]. Clinvar id is 1601724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLB	NM_175737.4 linkuse as main transcript	c.2183G>A	p.Arg728Gln	missense_variant	4/5	ENST00000257408.5	NP_783864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLB	ENST00000257408.5 linkuse as main transcript	c.2183G>A	p.Arg728Gln	missense_variant	4/5	1	NM_175737.4	ENSP00000257408	P1

Frequencies

GnomAD3 genomes

AF:

0.159

AC:

24135

AN:

152168

Hom.:

2243

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0719

Gnomad AMI

AF:

0.159

Gnomad AMR

AF:

0.216

Gnomad ASJ

AF:

0.254

Gnomad EAS

AF:

0.178

Gnomad SAS

AF:

0.173

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.190

Gnomad OTH

AF:

0.203

GnomAD3 exomes

AF:

0.183

AC:

43531

AN:

237952

Hom.:

4069

AF XY:

0.184

AC XY:

23969

AN XY:

130398

show subpopulations

Gnomad AFR exome

AF:

0.0707

Gnomad AMR exome

AF:

0.198

Gnomad ASJ exome

AF:

0.255

Gnomad EAS exome

AF:

0.185

Gnomad SAS exome

AF:

0.174

Gnomad FIN exome

AF:

0.165

Gnomad NFE exome

AF:

0.191

Gnomad OTH exome

AF:

0.196

GnomAD4 exome

AF:

0.186

AC:

269987

AN:

1453108

Hom.:

25670

Cov.:

AF XY:

0.186

AC XY:

134194

AN XY:

723124

show subpopulations

Gnomad4 AFR exome

AF:

0.0725

Gnomad4 AMR exome

AF:

0.202

Gnomad4 ASJ exome

AF:

0.249

Gnomad4 EAS exome

AF:

0.182

Gnomad4 SAS exome

AF:

0.171

Gnomad4 FIN exome

AF:

0.162

Gnomad4 NFE exome

AF:

0.189

Gnomad4 OTH exome

AF:

0.189

GnomAD4 genome

AF:

0.158

AC:

24132

AN:

152286

Hom.:

2245

Cov.:

AF XY:

0.157

AC XY:

11687

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0717

Gnomad4 AMR

AF:

0.216

Gnomad4 ASJ

AF:

0.254

Gnomad4 EAS

AF:

0.178

Gnomad4 SAS

AF:

0.172

Gnomad4 FIN

AF:

0.156

Gnomad4 NFE

AF:

0.190

Gnomad4 OTH

AF:

0.202

Alfa

AF:

0.182

Hom.:

1103

Bravo

AF:

0.160

TwinsUK

AF:

0.184

AC:

682

ALSPAC

AF:

0.184

AC:

710

ESP6500AA

AF:

0.0682

AC:

300

ESP6500EA

AF:

0.191

AC:

1645

ExAC

AF:

0.176

AC:

21236

Asia WGS

AF:

0.175

AC:

610

AN:

3478

EpiCase

AF:

0.198

EpiControl

AF:

0.204

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

7.6

DANN

Uncertain

0.98

DEOGEN2

Benign

0.019

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0029

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.18

REVEL

Benign

0.047

Sift

Benign

0.32

Sift4G

Benign

0.26

Polyphen

0.66

Vest4

0.075

MPC

0.68

ClinPred

0.0093

GERP RS

0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.56

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