chr12-4369345-G-A

Variant names:

• chr12-4369345-G-A
• rs71583766
• NM_020638.3:c.*998C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020638.3(FGF23):​c.*998C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000126 in 79,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: FGF23 NM_020638.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• Publications: 0 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), Ambry Genetics, Orphanet
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

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.*998C>T		3_prime_UTR	Exon 3 of 3	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.*998C>T		3_prime_UTR	Exon 3 of 3	ENSP00000237837.1	Q9GZV9
	ENSG00000285901	ENST00000674624.1		n.*1204+3063G>A		intron	N/A	ENSP00000501898.1	A0A6Q8PFP0
	ENSG00000285901	ENST00000648100.1		n.*1967+3063G>A		intron	N/A	ENSP00000497536.1	A0A3B3IT44

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000126 AC: 1 AN: 79394 Hom.: 0 Cov.: 0 AF XY: 0.0000274 AC XY: 1 AN XY: 36486

African (AFR) AF: 0.00 AC: 0 AN: 3816

American (AMR) AF: 0.00 AC: 0 AN: 2422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5030

East Asian (EAS) AF: 0.00 AC: 0 AN: 11176

South Asian (SAS) AF: 0.00 AC: 0 AN: 694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 62

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 490

European-Non Finnish (NFE) AF: 0.0000204 AC: 1 AN: 49070

Other (OTH) AF: 0.00 AC: 0 AN: 6634

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.43
DANN	Benign	0.70
PhyloP100		-1.2

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: rs71583766; hg19: chr12-4478511;