rs11940694

Variant names:

• chr4-39413373-A-G
• rs11940694
• NM_175737.4:c.825+5599A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3 BA1

The NM_175737.4(KLB):​c.825+5599A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.568 in 151,958 control chromosomes in the GnomAD database, including 24,948 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 0.57 (24948 hom., cov: 31)
• Consequence: KLB NM_175737.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.843
• Publications: 45 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 -7 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.591 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLB	NM_175737.4	MANE Select	c.825+5599A>G		intron	N/A	NP_783864.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLB	ENST00000257408.5	TSL:1 MANE Select	c.825+5599A>G		intron	N/A	ENSP00000257408.4

Frequencies

GnomAD3 genomes AF: 0.568 AC: 86230 AN: 151840 Hom.: 24915 Cov.: 31

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.669

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.422

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.550

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

GnomAD4 genome AF: 0.568 AC: 86299 AN: 151958 Hom.: 24948 Cov.: 31 AF XY: 0.564 AC XY: 41903 AN XY: 74280

African (AFR) AF: 0.582 AC: 24131 AN: 41444

American (AMR) AF: 0.450 AC: 6862 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 1596 AN: 3470

East Asian (EAS) AF: 0.444 AC: 2294 AN: 5162

South Asian (SAS) AF: 0.423 AC: 2036 AN: 4816

European-Finnish (FIN) AF: 0.663 AC: 6989 AN: 10544

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.596 AC: 40469 AN: 67958

Other (OTH) AF: 0.549 AC: 1157 AN: 2108

Alfa AF: 0.576 Hom.: 98294

Bravo AF: 0.555

Asia WGS AF: 0.504 AC: 1752 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	23
DANN	Benign	0.66
PhyloP100		-0.84
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.60		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11940694; hg19: chr4-39414993;