rs900563

Positions:

• chr4-39407796-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.122

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
KLB	NM_175737.4	c.825+22C>A		intron_variant		ENST00000257408.5	NP_783864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLB	ENST00000257408.5	c.825+22C>A		intron_variant		1	NM_175737.4	ENSP00000257408	P1

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30089 AN: 151994 Hom.: 3113 Cov.: 32

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

GnomAD3 exomes AF: 0.209 AC: 39734 AN: 190506 Hom.: 4365 AF XY: 0.206 AC XY: 21204 AN XY: 103078

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 SAS exome AF: 0.191

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.: 16 AF XY: 0.197 AC XY: 114251 AN XY: 579946

Gnomad4 AFR exome AF: 0.194

Gnomad4 AMR exome AF: 0.215

Gnomad4 ASJ exome AF: 0.158

Gnomad4 EAS exome AF: 0.374

Gnomad4 SAS exome AF: 0.186

Gnomad4 FIN exome AF: 0.237

Gnomad4 NFE exome AF: 0.190

Gnomad4 OTH exome AF: 0.209

GnomAD4 genome AF: 0.198 AC: 30107 AN: 152112 Hom.: 3115 Cov.: 32 AF XY: 0.200 AC XY: 14884 AN XY: 74366

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.205

Gnomad4 ASJ AF: 0.157

Gnomad4 EAS AF: 0.382

Gnomad4 SAS AF: 0.186

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.185

Gnomad4 OTH AF: 0.205

Alfa AF: 0.189 Hom.: 1841

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
DANN	Benign	0.59

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

Other links and lift over

dbSNP: rs900563; hg19: chr4-39409416; COSMIC: COSV57300163; COSMIC: COSV57300163;