12-4370383-G-A

Position:

chr12-4370383-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1131 hom., cov: 30)

Exomes 𝑓: 0.12 ( 10873 hom. )

Consequence

FGF23
NM_020638.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.649

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 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

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 id is 308803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-4370383-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGF23	NM_020638.3 linkuse as main transcript	c.716C>T	p.Thr239Met	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 linkuse as main transcript	c.716C>T	p.Thr239Met	missense_variant	3/3	1	NM_020638.3	ENSP00000237837	P1

Frequencies

GnomAD3 genomes

AF:

0.116

AC:

17617

AN:

152010

Hom.:

1130

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.129

AC:

32353

AN:

250586

Hom.:

2410

AF XY:

0.125

AC XY:

16977

AN XY:

135680

show subpopulations

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 SAS exome

AF:

0.111

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.:

AF XY:

0.117

AC XY:

84976

AN XY:

726990

show subpopulations

Gnomad4 AFR exome

AF:

0.0870

Gnomad4 AMR exome

AF:

0.201

Gnomad4 ASJ exome

AF:

0.0670

Gnomad4 EAS exome

AF:

0.163

Gnomad4 SAS exome

AF:

0.110

Gnomad4 FIN exome

AF:

0.121

Gnomad4 NFE exome

AF:

0.116

Gnomad4 OTH exome

AF:

0.116

GnomAD4 genome

AF:

0.116

AC:

17623

AN:

152128

Hom.:

1131

Cov.:

AF XY:

0.118

AC XY:

8759

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0815

Gnomad4 AMR

AF:

0.199

Gnomad4 ASJ

AF:

0.0625

Gnomad4 EAS

AF:

0.207

Gnomad4 SAS

AF:

0.111

Gnomad4 FIN

AF:

0.125

Gnomad4 NFE

AF:

0.113

Gnomad4 OTH

AF:

0.120

Alfa

AF:

0.110

Hom.:

1593

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

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 22419710) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	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). -

Autosomal dominant hypophosphatemic rickets

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

1.0

DANN

Benign

0.91

DEOGEN2

Benign

0.31

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0043

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0031

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.20

MutationTaster

Benign

1.0

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.11

REVEL

Benign

0.19

Sift

Benign

0.30

Sift4G

Benign

0.28

Polyphen

0.0010

Vest4

0.031

MPC

0.32

ClinPred

0.0019

GERP RS

-8.9

Varity_R

0.018

gMVP

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over