12-4368571-C-T

Variant names:

• chr12-4368571-C-T
• rs13312800
• NM_020638.3:c.*1772G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_020638.3(FGF23):​c.*1772G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 in 190,838 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (1 hom.)
• Consequence: FGF23 NM_020638.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.287
• Publications: 2 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 12-4368571-C-T is Benign according to our data. Variant chr12-4368571-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 308777.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00291 (442/152090) while in subpopulation AMR AF = 0.0051 (78/15286). AF 95% confidence interval is 0.00419. There are 0 homozygotes in GnomAd4. There are 197 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.*1772G>A		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.*1772G>A		3_prime_UTR	Exon 3 of 3	ENSP00000237837.1	Q9GZV9
	ENSG00000285901	ENST00000674624.1		n.*1204+2289C>T		intron	N/A	ENSP00000501898.1	A0A6Q8PFP0
	ENSG00000285901	ENST00000648100.1		n.*1967+2289C>T		intron	N/A	ENSP00000497536.1	A0A3B3IT44

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 441 AN: 151972 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00318

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00444

Gnomad OTH AF: 0.0101

GnomAD4 exome AF: 0.00423 AC: 164 AN: 38748 Hom.: 1 Cov.: 0 AF XY: 0.00457 AC XY: 82 AN XY: 17938

African (AFR) AF: 0.00 AC: 0 AN: 1560

American (AMR) AF: 0.00913 AC: 9 AN: 986

Ashkenazi Jewish (ASJ) AF: 0.00646 AC: 16 AN: 2476

East Asian (EAS) AF: 0.00 AC: 0 AN: 6762

South Asian (SAS) AF: 0.00307 AC: 1 AN: 326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30

Middle Eastern (MID) AF: 0.00413 AC: 1 AN: 242

European-Non Finnish (NFE) AF: 0.00531 AC: 123 AN: 23162

Other (OTH) AF: 0.00437 AC: 14 AN: 3204

GnomAD4 genome AF: 0.00291 AC: 442 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.00265 AC XY: 197 AN XY: 74378

African (AFR) AF: 0.000602 AC: 25 AN: 41494

American (AMR) AF: 0.00510 AC: 78 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00318 AC: 11 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4802

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10576

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00444 AC: 302 AN: 67980

Other (OTH) AF: 0.0104 AC: 22 AN: 2110

Alfa AF: 0.00307 Hom.: 0

Bravo AF: 0.00351

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal dominant hypophosphatemic rickets (1)
-	1	-	Tumoral calcinosis, hyperphosphatemic, familial, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.81
PhyloP100		0.29

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: rs13312800; hg19: chr12-4477737;