Genetic Variant KLB:p.Asp56Asn (chr4-39407115-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_175737.4(KLB):c.166G>A(p.Asp56Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000101 in 1,614,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

KLB
NM_175737.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 6.22

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0073911548).

BP6

Variant 4-39407115-G-A is Benign according to our data. Variant chr4-39407115-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3046714.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175737.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLB	NM_175737.4	MANE Select	c.166G>A	p.Asp56Asn	missense	Exon 1 of 5	NP_783864.1	Q86Z14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLB	ENST00000257408.5	TSL:1 MANE Select	c.166G>A	p.Asp56Asn	missense	Exon 1 of 5	ENSP00000257408.4	Q86Z14
	KLB	ENST00000859482.1		c.166G>A	p.Asp56Asn	missense	Exon 1 of 5	ENSP00000529541.1

Frequencies

GnomAD3 genomes

AF:

0.000513

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00166

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.000135

AC:

AN:

251442

AF XY:

0.0000736

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000581

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00215

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112002

Other (OTH)

AF:

0.000199

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000512

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00166

AC:

AN:

41570

American (AMR)

AF:

0.000327

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00190

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000327

Hom.:

Bravo

AF:

0.000744

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000181

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

KLB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

Eigen

Benign

-0.17

Eigen_PC

Benign

0.0013

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.76

M_CAP

Benign

0.0066

MetaRNN

Benign

0.0074

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

6.2

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.27

REVEL

Benign

0.053

Sift

Benign

0.13

Sift4G

Benign

0.31

Polyphen

0.0060

Vest4

0.058

MVP

0.48

MPC

0.57

ClinPred

0.070

GERP RS

4.2

PromoterAI

0.0060

Neutral

(source)

Varity_R

0.16

gMVP

0.62

Mutation Taster

=84/16

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over