chr12-4370564-G-C

Variant names:

• chr12-4370564-G-C
• rs28937882
• NM_020638.3:c.535C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_020638.3(FGF23):​c.535C>G​(p.Arg179Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R179Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FGF23 NM_020638.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.13
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• tumoral calcinosis, hyperphosphatemic, familial, 2

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285901 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 7 uncertain 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 chr12-4370563-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 36135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 autosomal dominant hypophosphatemic rickets, tumoral calcinosis, hyperphosphatemic, familial, 2, tumoral calcinosis, hyperphosphatemic, familial, 1.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF23	NM_020638.3	c.535C>G	p.Arg179Gly	missense_variant	Exon 3 of 3	ENST00000237837.2	NP_065689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF23	ENST00000237837.2	c.535C>G	p.Arg179Gly	missense_variant	Exon 3 of 3	1	NM_020638.3	ENSP00000237837.1
ENSG00000285901	ENST00000674624.1	n.*1204+4282G>C		intron_variant	Intron 9 of 9			ENSP00000501898.1
ENSG00000285901	ENST00000648100.1	n.*1967+4282G>C		intron_variant	Intron 11 of 11			ENSP00000497536.1
FGF23	ENST00000648269.1	n.*78C>G		downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	0.10
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.29	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.54
Sift	Benign	0.10	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.92	P
Vest4		0.62
MutPred		0.47		Loss of helix (P = 0.0444);
MVP		0.86
MPC		1.2
ClinPred		0.85	D
GERP RS		4.0
Varity_R		0.68
gMVP		0.57
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

dbSNP: rs28937882; hg19: chr12-4479730;