rs104894342

chr12-4379372-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PP3_Moderate PP5

The NM_020638.3(FGF23):c.211A>G(p.Ser71Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000391 in 1,610,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: FGF23 NM_020638.3 missense, splice_region
• Scores: Splicing: ADA: 0.3362
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1 O:1
• Conservation: PhyloP100: 5.20

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 Uncertain_significance. Variant got 5 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86
• PP5: Variant 12-4379372-T-C is Pathogenic according to our data. Variant chr12-4379372-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5027.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGF23	NM_020638.3	c.211A>G	p.Ser71Gly	missense_variant, splice_region_variant	1/3	ENST00000237837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGF23	ENST00000237837.2	c.211A>G	p.Ser71Gly	missense_variant, splice_region_variant	1/3	1	NM_020638.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249268 Hom.: 0 AF XY: 0.0000223 AC XY: 3 AN XY: 134810

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000418 AC: 61 AN: 1458550 Hom.: 0 Cov.: 31 AF XY: 0.0000372 AC XY: 27 AN XY: 725714

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: 0.0000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2016	The S71G variant in the FGF23 gene has been published previously in association with autosomal recessive familial tumoral calcinosis (Benet-Pagès et al., 2005; Larsson et al. 2005). The variant was not observed at any significant frequency 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. The variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown that S71G impairs O-glycosylation of the FGF23 protein and results in poor secretion from the Golgi complex (Benet-Pagès et al., 2005; Bergwitz et al., 2009). Therefore, this variant is likely pathogenic. -

Tumoral calcinosis, hyperphosphatemic, familial, 1 Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 19, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Tumoral calcinosis, hyperphosphatemic, familial, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2005

- -

Familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 16, 2014

The p.Ser71Gly variant in FGF23 has been reported in 2 homozygous individuals with hyperphosphatemic tumoral calcinosis and was found to segregate with disease in 1 affected homozygous relative (Benet-Pages 2005, Larsson 2005). This variant has been identified in 0.012% (1/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs104894342). In vitro functional studies suggest that the p.Ser71Gly variant may impact protein function (Garringer 2008, Bergwitz 2009); however, in vitro assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Ser71Gly variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ser71Gly variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.69
MVP		0.94
MPC		0.97
ClinPred		0.96	D
GERP RS		4.0
Varity_R		0.81
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.34
dbscSNV1_RF	Benign	0.27
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: rs104894342; hg19: chr12-4488538;