12-4379372-T-C

Variant names:

• chr12-4379372-T-C
• rs104894342
• NM_020638.3:c.211A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3 PM1 PP2 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). ClinVar reports functional evidence for this variant: "SCV000491242: 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" and additional evidence is available in ClinVar.

• 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:5 U:1 O:1
• Conservation: PhyloP100: 5.20
• Publications: 31 publications found

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]

FGF23 Gene-Disease associations (from GenCC):

• autosomal dominant hypophosphatemic rickets

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• tumoral calcinosis, hyperphosphatemic, familial, 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• tumoral calcinosis, hyperphosphatemic, familial, 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285901 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000491242: 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).
• PM1: In a chain Fibroblast growth factor 23 N-terminal peptide (size 154) in uniprot entity FGF23_HUMAN there are 11 pathogenic changes around while only 3 benign (79%) in NM_020638.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.39751 (below the threshold of 3.09). Trascript score misZ: 0.82334 (below the threshold of 3.09). GenCC associations: The gene is linked to tumoral calcinosis, hyperphosphatemic, familial, 2, autosomal dominant hypophosphatemic rickets, tumoral calcinosis, hyperphosphatemic, familial, 1.
• 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 VariationId is 5027.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020638.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF23	NM_020638.3	MANE Select	c.211A>G	p.Ser71Gly	missense splice_region	Exon 1 of 3	NP_065689.1	Q9GZV9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF23	ENST00000237837.2	TSL:1 MANE Select	c.211A>G	p.Ser71Gly	missense splice_region	Exon 1 of 3	ENSP00000237837.1	Q9GZV9
	ENSG00000285901	ENST00000674624.1		n.*1204+13090T>C		intron	N/A	ENSP00000501898.1	A0A6Q8PFP0
	ENSG00000285901	ENST00000648100.1		n.*1967+13090T>C		intron	N/A	ENSP00000497536.1	A0A3B3IT44

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

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 249268 AF XY: 0.0000223

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000540 AC: 60 AN: 1111586

Other (OTH) AF: 0.0000166 AC: 1 AN: 60356

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

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000327 Hom.: 0

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Autosomal dominant hypophosphatemic rickets;C4693863:Tumoral calcinosis, hyperphosphatemic, familial, 2 (1)
-	1	-	Familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome (1)
1	-	-	Tumoral calcinosis, hyperphosphatemic, familial, 1 (2)
1	-	-	Tumoral calcinosis, hyperphosphatemic, familial, 2 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.2
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
PromoterAI		0.20	Neutral
Varity_R		0.81
gMVP		0.90
Mutation Taster		=24/76	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894342; hg19: chr12-4488538;