12-4370572-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_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

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 5.10

Publications

72 publications found

Variant links:

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

FGF23 links:

ENSG00000285901 (HGNC:):

ENSG00000285901 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 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 chr12-4370573-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1072118.Status of the report is criteria_provided_single_submitter, 1 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.

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 VariationId is 5025.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF23	NM_020638.3 link	c.527G>A	p.Arg176Gln	missense_variant	Exon 3 of 3	ENST00000237837.2	NP_065689.1	Q9GZV9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FGF23	ENST00000237837.2 link	c.527G>A	p.Arg176Gln	missense_variant	Exon 3 of 3	1	NM_020638.3	ENSP00000237837.1	Q9GZV9
ENSG00000285901	ENST00000674624.1 link	n.*1204+4290C>T		intron_variant	Intron 9 of 9			ENSP00000501898.1	A0A6Q8PFP0
ENSG00000285901	ENST00000648100.1 link	n.*1967+4290C>T		intron_variant	Intron 11 of 11			ENSP00000497536.1	A0A3B3IT44
FGF23	ENST00000648269.1 link	n.*70G>A		downstream_gene_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461748

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727164

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111890

Other (OTH)

AF:

0.00

AC:

AN:

60390

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000896

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal dominant hypophosphatemic rickets

Pathogenic:1

Nov 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Jun 25, 2015

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.45

MutationAssessor

Uncertain

2.3

PhyloP100

5.1

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.32

REVEL

Uncertain

0.53

Sift

Benign

0.18

Sift4G

Uncertain

0.026

Polyphen

1.0

Vest4

0.79

MutPred

0.75

Loss of catalytic residue at R176 (P = 0.0423);

MVP

0.92

MPC

1.1

ClinPred

0.84

GERP RS

4.9

Varity_R

0.53

gMVP

0.65

Mutation Taster

=31/69

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over