NM_020638.3:c.716C>T

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal dominant hypophosphatemic rickets (1)
-	-	1	Tumoral calcinosis, hyperphosphatemic, familial, 2 (1)

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;