Genetic Variant KLB:p.Pro65Ala (chr4-39407142-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_175737.4(KLB):c.193C>G(p.Pro65Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,614,098 control chromosomes in the GnomAD database, including 33 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0078 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 23 hom. )

Consequence

KLB
NM_175737.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.01

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=0.002829045).

BP6

Variant 4-39407142-C-G is Benign according to our data. Variant chr4-39407142-C-G is described in ClinVar as [Benign]. Clinvar id is 713092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00782 (1191/152240) while in subpopulation AFR AF= 0.0232 (964/41544). AF 95% confidence interval is 0.022. There are 10 homozygotes in gnomad4. There are 533 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLB	NM_175737.4 link	c.193C>G	p.Pro65Ala	missense_variant	Exon 1 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.193C>G	p.Pro65Ala	missense_variant	Exon 1 of 5	1	NM_175737.4	ENSP00000257408.4		Q86Z14

Frequencies

GnomAD3 genomes

AF:

0.00778

AC:

1183

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0231

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.0119

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00374

AC:

940

AN:

251434

Hom.:

AF XY:

0.00308

AC XY:

419

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.0244

Gnomad AMR exome

AF:

0.00431

Gnomad ASJ exome

AF:

0.00198

Gnomad EAS exome

AF:

0.0129

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000906

Gnomad OTH exome

AF:

0.00456

GnomAD4 exome

AF:

0.00172

AC:

2514

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

1188

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0227

Gnomad4 AMR exome

AF:

0.00470

Gnomad4 ASJ exome

AF:

0.00161

Gnomad4 EAS exome

AF:

0.00751

Gnomad4 SAS exome

AF:

0.000371

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000766

Gnomad4 OTH exome

AF:

0.00464

GnomAD4 genome

AF:

0.00782

AC:

1191

AN:

152240

Hom.:

Cov.:

AF XY:

0.00716

AC XY:

533

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0232

Gnomad4 AMR

AF:

0.00576

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.0118

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000735

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00226

Hom.:

Bravo

AF:

0.00880

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0238

AC:

105

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00396

AC:

481

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.000981

EpiControl

AF:

0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 06, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.74

CADD

Benign

DANN

Benign

0.69

DEOGEN2

Benign

0.016

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.61

REVEL

Benign

0.093

Sift

Benign

0.46

Sift4G

Benign

1.0

Polyphen

0.024

Vest4

0.15

MVP

0.35

MPC

0.57

ClinPred

0.0029

GERP RS

4.2

Varity_R

0.043

gMVP

0.50

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