Genetic Variant FGF23:c.212-37_212-36insC (chr12-4372733-C-CG) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_020638.3(FGF23):c.212-37_212-36insC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,345,846 control chromosomes in the GnomAD database, including 11,887 homozygotes. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.10 ( 960 hom., cov: 30)

Exomes 𝑓: 0.13 ( 10927 hom. )

Consequence

FGF23
NM_020638.3 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.23

Publications

9 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: Benign. The variant received -10 ACMG points.

BP6

Variant 12-4372733-C-CG is Benign according to our data. Variant chr12-4372733-C-CG is described in ClinVar as Benign. ClinVar VariationId is 1238224.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF23	NM_020638.3 link	c.212-37_212-36insC		intron_variant	Intron 1 of 2	ENST00000237837.2	NP_065689.1	Q9GZV9

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
FGF23	ENST00000237837.2 link	c.212-37_212-36insC	intron_variant	Intron 1 of 2	1	NM_020638.3	ENSP00000237837.1	Q9GZV9
ENSG00000285901	ENST00000674624.1 link	n.1204+6451_1204+6452insG	intron_variant	Intron 9 of 9			ENSP00000501898.1	A0A6Q8PFP0
FGF23	ENST00000648269.1 link	n.1675_1676insC	non_coding_transcript_exon_variant	Exon 1 of 2
ENSG00000285901	ENST00000648100.1 link	n.1967+6451_1967+6452insG	intron_variant	Intron 11 of 11			ENSP00000497536.1	A0A3B3IT44

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15549

AN:

152070

Hom.:

957

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0500

Gnomad AMI

AF:

0.0855

Gnomad AMR

AF:

0.0759

Gnomad ASJ

AF:

0.0903

Gnomad EAS

AF:

0.0338

Gnomad SAS

AF:

0.225

Gnomad FIN

AF:

0.132

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.0976

GnomAD2 exomes

AF:

0.121

AC:

30112

AN:

249886

AF XY:

0.128

show subpopulations

Gnomad AFR exome

AF:

0.0498

Gnomad AMR exome

AF:

0.0589

Gnomad ASJ exome

AF:

0.0925

Gnomad EAS exome

AF:

0.0357

Gnomad FIN exome

AF:

0.139

Gnomad NFE exome

AF:

0.136

Gnomad OTH exome

AF:

0.123

GnomAD4 exome

AF:

0.128

AC:

152652

AN:

1193656

Hom.:

10927

Cov.:

AF XY:

0.131

AC XY:

79693

AN XY:

606838

show subpopulations

African (AFR)

AF:

0.0501

AC:

1417

AN:

28304

American (AMR)

AF:

0.0617

AC:

2741

AN:

44442

Ashkenazi Jewish (ASJ)

AF:

0.0910

AC:

2220

AN:

24402

East Asian (EAS)

AF:

0.0421

AC:

1622

AN:

38512

South Asian (SAS)

AF:

0.211

AC:

17037

AN:

80912

European-Finnish (FIN)

AF:

0.140

AC:

7425

AN:

52924

Middle Eastern (MID)

AF:

0.0896

AC:

467

AN:

5214

European-Non Finnish (NFE)

AF:

0.131

AC:

113789

AN:

867408

Other (OTH)

AF:

0.115

AC:

5934

AN:

51538

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

6900

13800

20700

27600

34500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3562

7124

10686

14248

17810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.102

AC:

15562

AN:

152190

Hom.:

960

Cov.:

AF XY:

0.102

AC XY:

7583

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0500

AC:

2078

AN:

41536

American (AMR)

AF:

0.0757

AC:

1158

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0903

AC:

313

AN:

3468

East Asian (EAS)

AF:

0.0338

AC:

175

AN:

5170

South Asian (SAS)

AF:

0.226

AC:

1090

AN:

4818

European-Finnish (FIN)

AF:

0.132

AC:

1402

AN:

10596

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.133

AC:

9031

AN:

67988

Other (OTH)

AF:

0.0966

AC:

204

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

702

1404

2106

2808

3510

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

186

372

558

744

930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.120

Hom.:

263

Bravo

AF:

0.0924

Asia WGS

AF:

0.115

AC:

403

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.2

BranchPoint Hunter

1.0

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over