rs12647895

Positions:

• chr4-39408562-T-A
• chr4-39408562-T-G

Variant summary

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

The NM_175737.4(KLB):​c.825+788T>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 152,144 control chromosomes in the GnomAD database, including 3,123 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 (3123 hom., cov: 32)
• Consequence: KLB NM_175737.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.256

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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLB	NM_175737.4	c.825+788T>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+788T>A		intron_variant		1	NM_175737.4	ENSP00000257408	P1

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30115 AN: 152026 Hom.: 3121 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.201

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.198 AC: 30133 AN: 152144 Hom.: 3123 Cov.: 32 AF XY: 0.200 AC XY: 14894 AN XY: 74386

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.205

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.384

Gnomad4 SAS AF: 0.186

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.185

Gnomad4 OTH AF: 0.205

Alfa AF: 0.198 Hom.: 386

Bravo AF: 0.198

Asia WGS AF: 0.332 AC: 1143 AN: 3458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.1
DANN	Benign	0.69

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: rs12647895; hg19: chr4-39410182;