Variant chr4-39448609-C-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.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. 14/20 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 0.29 ( 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

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=0.002471596).

BP6

Variant 4-39448609-C-A is Benign according to our data. Variant chr4-39448609-C-A is described in ClinVar as [Benign]. Clinvar id 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/exons	MANE	Protein	UniProt
KLB	NM_175737.4 linkuse as main transcript	c.3058C>A	p.Gln1020Lys	missense_variant	5/5	ENST00000257408.5	NP_783864.1	Q86Z14B4DYH5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLB	ENST00000257408.5 linkuse as main transcript	c.3058C>A	p.Gln1020Lys	missense_variant	5/5	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

GnomAD3 exomes

AF:

0.350

AC:

87813

AN:

251232

Hom.:

16250

AF XY:

0.352

AC XY:

47818

AN XY:

135806

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 SAS exome

AF:

0.434

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

Gnomad4 AFR exome

AF:

0.137

Gnomad4 AMR exome

AF:

0.440

Gnomad4 ASJ exome

AF:

0.236

Gnomad4 EAS exome

AF:

0.390

Gnomad4 SAS exome

AF:

0.427

Gnomad4 FIN exome

AF:

0.372

Gnomad4 NFE exome

AF:

0.327

Gnomad4 OTH exome

AF:

0.302

GnomAD4 genome

AF:

0.290

AC:

44087

AN:

152054

Hom.:

7057

Cov.:

AF XY:

0.297

AC XY:

22090

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.150

Gnomad4 AMR

AF:

0.369

Gnomad4 ASJ

AF:

0.238

Gnomad4 EAS

AF:

0.394

Gnomad4 SAS

AF:

0.444

Gnomad4 FIN

AF:

0.371

Gnomad4 NFE

AF:

0.328

Gnomad4 OTH

AF:

0.274

Alfa

AF:

0.319

Hom.:

19848

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2021	- -

KLB-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

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

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

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

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