chr12-4372733-C-CG

Variant names:

• chr12-4372733-C-CG
• rs3832879
• NM_020638.3:c.212-37_212-36insC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.23
• Publications: 9 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• tumoral calcinosis, hyperphosphatemic, familial, 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• tumoral calcinosis, hyperphosphatemic, familial, 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285901 (HGNC:):

ACMG classification

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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF23	NM_020638.3	MANE Select	c.212-37_212-36insC		intron	N/A	NP_065689.1	Q9GZV9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF23	ENST00000237837.2	TSL:1 MANE Select	c.212-37_212-36insC		intron	N/A	ENSP00000237837.1	Q9GZV9
	ENSG00000285901	ENST00000674624.1		n.*1204+6451_*1204+6452insG		intron	N/A	ENSP00000501898.1	A0A6Q8PFP0
	FGF23	ENST00000648269.1		n.1675_1676insC		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15549 AN: 152070 Hom.: 957 Cov.: 30

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

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.: 17 AF XY: 0.131 AC XY: 79693 AN XY: 606838

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

GnomAD4 genome AF: 0.102 AC: 15562 AN: 152190 Hom.: 960 Cov.: 30 AF XY: 0.102 AC XY: 7583 AN XY: 74422

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: 33 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9031 AN: 67988

Other (OTH) AF: 0.0966 AC: 204 AN: 2112

Alfa AF: 0.120 Hom.: 263

Bravo AF: 0.0924

Asia WGS AF: 0.115 AC: 403 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.2
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3832879; hg19: chr12-4481899;