rs3832879

Variant names:

• chr12-4372733-C-CA
• rs3832879
• NM_020638.3:c.212-37_212-36insT

Your query was ambiguous. Multiple possible variants found:

• chr12-4372733-C-CA
• chr12-4372733-C-CG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020638.3(FGF23):​c.212-37_212-36insT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000418 in 1,194,768 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: FGF23 NM_020638.3 intron
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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_212-36insT		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_212-36insT		intron	N/A	ENSP00000237837.1	Q9GZV9
	ENSG00000285901	ENST00000674624.1		n.*1204+6451_*1204+6452insA		intron	N/A	ENSP00000501898.1	A0A6Q8PFP0
	FGF23	ENST00000648269.1		n.1675_1676insT		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249886 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000418 AC: 5 AN: 1194768 Hom.: 0 Cov.: 17 AF XY: 0.00000494 AC XY: 3 AN XY: 607352

African (AFR) AF: 0.00 AC: 0 AN: 28314

American (AMR) AF: 0.00 AC: 0 AN: 44446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24408

East Asian (EAS) AF: 0.00 AC: 0 AN: 38514

South Asian (SAS) AF: 0.0000247 AC: 2 AN: 80938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5214

European-Non Finnish (NFE) AF: 0.00000230 AC: 2 AN: 868420

Other (OTH) AF: 0.0000194 AC: 1 AN: 51576

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.2
BranchPoint Hunter		1.0

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;