dbSNP rs900563: KLB:c.825+22C>A (chr4-39407796-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_175737.4(KLB):c.825+22C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 1,332,372 control chromosomes in the GnomAD database, including 27,180 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.20 ( 3115 hom., cov: 32)

Exomes 𝑓: 0.20 ( 24065 hom. )

Consequence

KLB
NM_175737.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.122

Publications

10 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLB	NM_175737.4 link	c.825+22C>A		intron_variant	Intron 1 of 4	ENST00000257408.5	NP_783864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLB	ENST00000257408.5 link	c.825+22C>A		intron_variant	Intron 1 of 4	1	NM_175737.4	ENSP00000257408.4

Frequencies

GnomAD3 genomes

AF:

0.198

AC:

30089

AN:

151994

Hom.:

3113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.191

Gnomad AMI

AF:

0.185

Gnomad AMR

AF:

0.206

Gnomad ASJ

AF:

0.157

Gnomad EAS

AF:

0.382

Gnomad SAS

AF:

0.186

Gnomad FIN

AF:

0.227

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.185

Gnomad OTH

AF:

0.201

GnomAD2 exomes

AF:

0.209

AC:

39734

AN:

190506

AF XY:

0.206

show subpopulations

Gnomad AFR exome

AF:

0.189

Gnomad AMR exome

AF:

0.209

Gnomad ASJ exome

AF:

0.165

Gnomad EAS exome

AF:

0.364

Gnomad FIN exome

AF:

0.238

Gnomad NFE exome

AF:

0.185

Gnomad OTH exome

AF:

0.212

GnomAD4 exome

AF:

0.198

AC:

234107

AN:

1180260

Hom.:

24065

Cov.:

AF XY:

0.197

AC XY:

114251

AN XY:

579946

show subpopulations

African (AFR)

AF:

0.194

AC:

5344

AN:

27566

American (AMR)

AF:

0.215

AC:

6207

AN:

28882

Ashkenazi Jewish (ASJ)

AF:

0.158

AC:

3003

AN:

18990

East Asian (EAS)

AF:

0.374

AC:

14039

AN:

37566

South Asian (SAS)

AF:

0.186

AC:

9229

AN:

49718

European-Finnish (FIN)

AF:

0.237

AC:

10810

AN:

45518

Middle Eastern (MID)

AF:

0.189

AC:

923

AN:

4890

European-Non Finnish (NFE)

AF:

0.190

AC:

174325

AN:

918104

Other (OTH)

AF:

0.209

AC:

10227

AN:

49026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

9357

18715

28072

37430

46787

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6596

13192

19788

26384

32980

<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:

0.198

AC:

30107

AN:

152112

Hom.:

3115

Cov.:

AF XY:

0.200

AC XY:

14884

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.191

AC:

7912

AN:

41498

American (AMR)

AF:

0.205

AC:

3130

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.157

AC:

546

AN:

3470

East Asian (EAS)

AF:

0.382

AC:

1976

AN:

5174

South Asian (SAS)

AF:

0.186

AC:

895

AN:

4818

European-Finnish (FIN)

AF:

0.227

AC:

2406

AN:

10576

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.185

AC:

12582

AN:

67988

Other (OTH)

AF:

0.205

AC:

433

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1237

2474

3712

4949

6186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

328

656

984

1312

1640

<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:

0.191

Hom.:

5962

Bravo

AF:

0.198

Asia WGS

AF:

0.331

AC:

1146

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.34

(source)

DANN

Benign

0.59

PhyloP100

-0.12

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over