rs1458254

Positions:

• chr4-39445187-C-T

Variant summary

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

The ENST00000257408.5(KLB):​c.1606-1145C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 152,108 control chromosomes in the GnomAD database, including 2,264 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 0.16 (2264 hom., cov: 31)
• Consequence: KLB ENST00000257408.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.110

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=-0.61).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLB	NM_175737.4	c.1606-1145C>T		intron_variant		ENST00000257408.5	NP_783864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLB	ENST00000257408.5	c.1606-1145C>T		intron_variant		1	NM_175737.4	ENSP00000257408	P1

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24778 AN: 151990 Hom.: 2258 Cov.: 31

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.0705

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.148

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

GnomAD4 genome AF: 0.163 AC: 24804 AN: 152108 Hom.: 2264 Cov.: 31 AF XY: 0.158 AC XY: 11782 AN XY: 74354

Gnomad4 AFR AF: 0.240

Gnomad4 AMR AF: 0.124

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.0707

Gnomad4 SAS AF: 0.109

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.147

Gnomad4 OTH AF: 0.146

Alfa AF: 0.147 Hom.: 874

Bravo AF: 0.169

Asia WGS AF: 0.0830 AC: 290 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.4
DANN	Benign	0.87

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: rs1458254; hg19: chr4-39446807;