rs7955866

Variant names:

• chr12-4370383-G-A
• rs7955866
• NM_020638.3:c.716C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_020638.3(FGF23):​c.716C>T​(p.Thr239Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,613,426 control chromosomes in the GnomAD database, including 12,004 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T239T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1131 hom., cov: 30)
  • Exomes 𝑓: 0.12 (10873 hom.)
• Consequence: FGF23 NM_020638.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.649
• Publications: 46 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: Benign. The variant received -19 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0031498075).
• BP6: Variant 12-4370383-G-A is Benign according to our data. Variant chr12-4370383-G-A is described in ClinVar as Benign. ClinVar VariationId is 308803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF23	NM_020638.3	MANE Select	c.716C>T	p.Thr239Met	missense	Exon 3 of 3	NP_065689.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF23	ENST00000237837.2	TSL:1 MANE Select	c.716C>T	p.Thr239Met	missense	Exon 3 of 3	ENSP00000237837.1
	ENSG00000285901	ENST00000674624.1		n.*1204+4101G>A		intron	N/A	ENSP00000501898.1
	ENSG00000285901	ENST00000648100.1		n.*1967+4101G>A		intron	N/A	ENSP00000497536.1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17617 AN: 152010 Hom.: 1130 Cov.: 30

Gnomad AFR AF: 0.0815

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.0625

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.122

GnomAD2 exomes AF: 0.129 AC: 32353 AN: 250586 AF XY: 0.125

Gnomad AFR exome AF: 0.0859

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.0662

Gnomad EAS exome AF: 0.208

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.118 AC: 172497 AN: 1461298 Hom.: 10873 Cov.: 33 AF XY: 0.117 AC XY: 84976 AN XY: 726990

African (AFR) AF: 0.0870 AC: 2914 AN: 33480

American (AMR) AF: 0.201 AC: 9005 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0670 AC: 1751 AN: 26136

East Asian (EAS) AF: 0.163 AC: 6457 AN: 39700

South Asian (SAS) AF: 0.110 AC: 9452 AN: 86254

European-Finnish (FIN) AF: 0.121 AC: 6423 AN: 52910

Middle Eastern (MID) AF: 0.0671 AC: 387 AN: 5768

European-Non Finnish (NFE) AF: 0.116 AC: 129101 AN: 1111942

Other (OTH) AF: 0.116 AC: 7007 AN: 60386

GnomAD4 genome AF: 0.116 AC: 17623 AN: 152128 Hom.: 1131 Cov.: 30 AF XY: 0.118 AC XY: 8759 AN XY: 74366

African (AFR) AF: 0.0815 AC: 3383 AN: 41500

American (AMR) AF: 0.199 AC: 3042 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0625 AC: 217 AN: 3472

East Asian (EAS) AF: 0.207 AC: 1068 AN: 5168

South Asian (SAS) AF: 0.111 AC: 535 AN: 4830

European-Finnish (FIN) AF: 0.125 AC: 1320 AN: 10594

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7701 AN: 67962

Other (OTH) AF: 0.120 AC: 254 AN: 2112

Alfa AF: 0.111 Hom.: 2169

Bravo AF: 0.120

TwinsUK AF: 0.122 AC: 451

ALSPAC AF: 0.125 AC: 482

ESP6500AA AF: 0.0901 AC: 397

ESP6500EA AF: 0.113 AC: 973

ExAC AF: 0.123 AC: 14986

Asia WGS AF: 0.165 AC: 575 AN: 3478

EpiCase AF: 0.103

EpiControl AF: 0.103

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22419710)

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Thr239Met in exon 3 of FGF23: This variant is not expected to have clinical si gnificance because it has been identified in 20.38% (2358/11572) of Latino chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs7955866).

Jul 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal dominant hypophosphatemic rickets Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Tumoral calcinosis, hyperphosphatemic, familial, 2 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.0
DANN	Benign	0.91
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-0.65
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.19
Sift	Benign	0.30	T
Sift4G	Benign	0.28	T
Polyphen		0.0010	B
Vest4		0.031
MPC		0.32
ClinPred		0.0019	T
GERP RS		-8.9
Varity_R		0.018
gMVP		0.19
Mutation Taster		=98/2	polymorphism (auto)

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: rs7955866; hg19: chr12-4479549; COSMIC: COSV52976898;