chr4-39445187-C-T

Variant names:

• chr4-39445187-C-T
• rs1458254
• NM_175737.4:c.1606-1145C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_175737.4(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 NM_175737.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.110
• Publications: 7 publications found

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

Our verdict: Benign. The variant received -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.

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.1606-1145C>T		intron	N/A	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.1606-1145C>T		intron	N/A	ENSP00000257408.4	Q86Z14
	KLB	ENST00000859482.1		c.1606-1172C>T		intron	N/A	ENSP00000529541.1

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

African (AFR) AF: 0.240 AC: 9934 AN: 41450

American (AMR) AF: 0.124 AC: 1890 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 377 AN: 3468

East Asian (EAS) AF: 0.0707 AC: 366 AN: 5176

South Asian (SAS) AF: 0.109 AC: 528 AN: 4822

European-Finnish (FIN) AF: 0.109 AC: 1154 AN: 10596

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 9961 AN: 67990

Other (OTH) AF: 0.146 AC: 309 AN: 2116

Alfa AF: 0.148 Hom.: 979

Bravo AF: 0.169

Asia WGS AF: 0.0830 AC: 290 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.4
DANN	Benign	0.87
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1458254; hg19: chr4-39446807;