12-4370572-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_020638.3(FGF23):c.527G>A(p.Arg176Gln) 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. R176P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FGF23 NM_020638.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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 10 ACMG points.

• PM1: In a chain Fibroblast growth factor 23 N-terminal peptide (size 154) in uniprot entity FGF23_HUMAN there are 18 pathogenic changes around while only 1 benign (95%) 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 chr12-4370573-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1072118.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 12-4370572-C-T is Pathogenic according to our data. Variant chr12-4370572-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5025.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGF23	NM_020638.3	c.527G>A	p.Arg176Gln	missense_variant	3/3	ENST00000237837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGF23	ENST00000237837.2	c.527G>A	p.Arg176Gln	missense_variant	3/3	1	NM_020638.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461748 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727164

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000896 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant hypophosphatemic rickets Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2000

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 25, 2015

The R176Q missense variant in the FGF23 gene has been reported previously in association with autosomal dominant hypophosphatemic rickets (ADHR) (Seton et al., 2013, The ADHR Consortium, 2000). The R176Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Missense variants at the same residue (R176W) and in nearby residues (R179Q, R179W) have been reported in the Human Gene Mutation Database in association with ADHR (Stenson et al., 2014). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.80	A
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.32	N
REVEL	Uncertain	0.53
Sift	Benign	0.18	T
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.75		Loss of catalytic residue at R176 (P = 0.0423);
MVP		0.92
MPC		1.1
ClinPred		0.84	D
GERP RS		4.9
Varity_R		0.53
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs104894347; hg19: chr12-4479738; COSMIC: COSV52976124;