12-4370516-G-C

Position:

• chr12-4370516-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_020638.3(FGF23):​c.583C>G​(p.Pro195Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FGF23 NM_020638.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.83

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]

ENSG00000285901 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a chain Fibroblast growth factor 23 (size 226) in uniprot entity FGF23_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_020638.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31779313).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGF23	NM_020638.3	c.583C>G	p.Pro195Ala	missense_variant	3/3	ENST00000237837.2	NP_065689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGF23	ENST00000237837.2	c.583C>G	p.Pro195Ala	missense_variant	3/3	1	NM_020638.3	ENSP00000237837.1
ENSG00000285901	ENST00000674624.1	n.*1204+4234G>C		intron_variant				ENSP00000501898.1
ENSG00000285901	ENST00000648100.1	n.*1967+4234G>C		intron_variant				ENSP00000497536.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246590 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134168

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459568 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725732

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.0	M
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.25
Sift	Benign	0.058	T
Sift4G	Benign	0.35	T
Polyphen		0.037	B
Vest4		0.22
MutPred		0.23		Gain of MoRF binding (P = 0.0632);
MVP		0.94
MPC		0.32
ClinPred		0.079	T
GERP RS		3.0
Varity_R		0.15
gMVP		0.26

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

Publications

LitVar

Other links and lift over

dbSNP: rs13312793; hg19: chr12-4479682;