rs17618244

Positions:

• chr4-39446909-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_175737.4(KLB):​c.2183G>A​(p.Arg728Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 1,605,394 control chromosomes in the GnomAD database, including 27,915 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (2245 hom., cov: 33)
  • Exomes 𝑓: 0.19 (25670 hom.)
• Consequence: KLB NM_175737.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.426

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029337704).
• BP6: Variant 4-39446909-G-A is Benign according to our data. Variant chr4-39446909-G-A is described in ClinVar as [Benign]. Clinvar id is 1601724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLB	NM_175737.4	c.2183G>A	p.Arg728Gln	missense_variant	4/5	ENST00000257408.5	NP_783864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLB	ENST00000257408.5	c.2183G>A	p.Arg728Gln	missense_variant	4/5	1	NM_175737.4	ENSP00000257408	P1

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24135 AN: 152168 Hom.: 2243 Cov.: 33

Gnomad AFR AF: 0.0719

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.203

GnomAD3 exomes AF: 0.183 AC: 43531 AN: 237952 Hom.: 4069 AF XY: 0.184 AC XY: 23969 AN XY: 130398

Gnomad AFR exome AF: 0.0707

Gnomad AMR exome AF: 0.198

Gnomad ASJ exome AF: 0.255

Gnomad EAS exome AF: 0.185

Gnomad SAS exome AF: 0.174

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.191

Gnomad OTH exome AF: 0.196

GnomAD4 exome AF: 0.186 AC: 269987 AN: 1453108 Hom.: 25670 Cov.: 34 AF XY: 0.186 AC XY: 134194 AN XY: 723124

Gnomad4 AFR exome AF: 0.0725

Gnomad4 AMR exome AF: 0.202

Gnomad4 ASJ exome AF: 0.249

Gnomad4 EAS exome AF: 0.182

Gnomad4 SAS exome AF: 0.171

Gnomad4 FIN exome AF: 0.162

Gnomad4 NFE exome AF: 0.189

Gnomad4 OTH exome AF: 0.189

GnomAD4 genome AF: 0.158 AC: 24132 AN: 152286 Hom.: 2245 Cov.: 33 AF XY: 0.157 AC XY: 11687 AN XY: 74472

Gnomad4 AFR AF: 0.0717

Gnomad4 AMR AF: 0.216

Gnomad4 ASJ AF: 0.254

Gnomad4 EAS AF: 0.178

Gnomad4 SAS AF: 0.172

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.190

Gnomad4 OTH AF: 0.202

Alfa AF: 0.182 Hom.: 1103

Bravo AF: 0.160

TwinsUK AF: 0.184 AC: 682

ALSPAC AF: 0.184 AC: 710

ESP6500AA AF: 0.0682 AC: 300

ESP6500EA AF: 0.191 AC: 1645

ExAC AF: 0.176 AC: 21236

Asia WGS AF: 0.175 AC: 610 AN: 3478

EpiCase AF: 0.198

EpiControl AF: 0.204

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.6
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.047
Sift	Benign	0.32	T
Sift4G	Benign	0.26	T
Polyphen		0.66	P
Vest4		0.075
MPC		0.68
ClinPred		0.0093	T
GERP RS		0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.56

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: rs17618244; hg19: chr4-39448529; COSMIC: COSV57300791;