rs193922702

Positions:

• chr12-4370563-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_020638.3(FGF23):​c.536G>A​(p.Arg179Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R179W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FGF23 NM_020638.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.10

Genes affected

FGF23 (HGNC:3680): (fibroblast growth factor 23) This gene encodes a member of the fibroblast growth factor family of proteins, which possess broad mitogenic and cell survival activities and are involved in a variety of biological processes. The product of this gene regulates phosphate homeostasis and transport in the kidney. The full-length, functional protein may be deactivated via cleavage into N-terminal and C-terminal chains. Mutation of this cleavage site causes autosomal dominant hypophosphatemic rickets (ADHR). Mutations in this gene are also associated with hyperphosphatemic familial tumoral calcinosis (HFTC). [provided by RefSeq, Feb 2013]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a site Cleavage; by proprotein convertases (size 1) in uniprot entity FGF23_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_020638.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-4370564-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799
• PP5: Variant 12-4370563-C-T is Pathogenic according to our data. Variant chr12-4370563-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 36135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGF23	NM_020638.3	c.536G>A	p.Arg179Gln	missense_variant	3/3	ENST00000237837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGF23	ENST00000237837.2	c.536G>A	p.Arg179Gln	missense_variant	3/3	1	NM_020638.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249544 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135418

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant hypophosphatemic rickets Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 05, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Heterozygous Missense variant c.536G>A in Exon 3 of the FGF23 gene that results in the amino acid substitution p.Arg179Gln was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID: 36135]. The observed variation has previously been reported in autosomal dominant hypophosphatemic rickets patients (ADHR Consortium, 2000). Experimental studies have shown that the observed mutation significantly decrease plasma Pi and renal Na/Pi cotransport activity and also the level of type-IIc Na/Pi cotransporter protein in brush-border membrane vesicles (BBMVs) in Kidney (Segawa H, et.al., 2003). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

Hypophosphatemic rickets Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi

Mar 07, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 08, 2021

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FGF23 function (PMID: 11409890, 12130585, 12851820). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FGF23 protein function. ClinVar contains an entry for this variant (Variation ID: 36135). This missense change has been observed in individuals with autosomal dominant hypophosphatemic rickets (PMID: 11062477, 21880793, 26186302). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs193922702, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 179 of the FGF23 protein (p.Arg179Gln). -

Autosomal dominant hypophosphatemic rickets;C4693863:Tumoral calcinosis, hyperphosphatemic, familial, 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.84	N
REVEL	Uncertain	0.56
Sift	Benign	0.051	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.73		Loss of solvent accessibility (P = 0.0769);
MVP		0.88
MPC		1.1
ClinPred		0.88	D
GERP RS		4.9
Varity_R		0.68
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs193922702; hg19: chr12-4479729; COSMIC: COSV52975411;