rs4975017

Positions:

• chr4-39448609-C-A

Variant summary

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

The ENST00000257408.5(KLB):​c.3058C>A​(p.Gln1020Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,613,676 control chromosomes in the GnomAD database, including 89,808 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.29 (7057 hom., cov: 33)
  • Exomes 𝑓: 0.33 (82751 hom.)
• Consequence: KLB ENST00000257408.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.30

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=0.002471596).
• BP6: Variant 4-39448609-C-A is Benign according to our data. Variant chr4-39448609-C-A is described in ClinVar as [Benign]. Clinvar id is 1287276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLB	NM_175737.4	c.3058C>A	p.Gln1020Lys	missense_variant	5/5	ENST00000257408.5	NP_783864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLB	ENST00000257408.5	c.3058C>A	p.Gln1020Lys	missense_variant	5/5	1	NM_175737.4	ENSP00000257408	P1

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44061 AN: 151936 Hom.: 7049 Cov.: 33

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.368

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.270

GnomAD3 exomes AF: 0.350 AC: 87813 AN: 251232 Hom.: 16250 AF XY: 0.352 AC XY: 47818 AN XY: 135806

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.455

Gnomad ASJ exome AF: 0.228

Gnomad EAS exome AF: 0.389

Gnomad SAS exome AF: 0.434

Gnomad FIN exome AF: 0.369

Gnomad NFE exome AF: 0.326

Gnomad OTH exome AF: 0.327

GnomAD4 exome AF: 0.332 AC: 485216 AN: 1461622 Hom.: 82751 Cov.: 36 AF XY: 0.335 AC XY: 243371 AN XY: 727118

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.440

Gnomad4 ASJ exome AF: 0.236

Gnomad4 EAS exome AF: 0.390

Gnomad4 SAS exome AF: 0.427

Gnomad4 FIN exome AF: 0.372

Gnomad4 NFE exome AF: 0.327

Gnomad4 OTH exome AF: 0.302

GnomAD4 genome AF: 0.290 AC: 44087 AN: 152054 Hom.: 7057 Cov.: 33 AF XY: 0.297 AC XY: 22090 AN XY: 74334

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.369

Gnomad4 ASJ AF: 0.238

Gnomad4 EAS AF: 0.394

Gnomad4 SAS AF: 0.444

Gnomad4 FIN AF: 0.371

Gnomad4 NFE AF: 0.328

Gnomad4 OTH AF: 0.274

Alfa AF: 0.319 Hom.: 19848

Bravo AF: 0.280

TwinsUK AF: 0.330 AC: 1223

ALSPAC AF: 0.334 AC: 1286

ESP6500AA AF: 0.155 AC: 684

ESP6500EA AF: 0.325 AC: 2792

ExAC AF: 0.343 AC: 41621

Asia WGS AF: 0.435 AC: 1513 AN: 3478

EpiCase AF: 0.317

EpiControl AF: 0.315

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2021	- -

KLB-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	13
DANN	Benign	0.12
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.95	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.068
Sift	Benign	1.0	T
Sift4G	Benign	0.88	T
Polyphen		0.049	B
Vest4		0.086
MPC		0.0056
ClinPred		0.0078	T
GERP RS		2.8
Varity_R		0.12
gMVP		0.27

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: rs4975017; hg19: chr4-39450229; COSMIC: COSV57304637; COSMIC: COSV57304637;