NM_020638.3:c.315+196A>G

Variant names:

• chr12-4372398-T-C
• rs11063118
• NM_020638.3:c.315+196A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_020638.3(FGF23):​c.315+196A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 151,982 control chromosomes in the GnomAD database, including 3,892 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.22 (3892 hom., cov: 31)
• Consequence: FGF23 NM_020638.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.40
• Publications: 6 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 12-4372398-T-C is Benign according to our data. Variant chr12-4372398-T-C is described in ClinVar as Benign. ClinVar VariationId is 1259786.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.33 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.315+196A>G		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.315+196A>G		intron	N/A	ENSP00000237837.1	Q9GZV9
	ENSG00000285901	ENST00000674624.1		n.*1204+6116T>C		intron	N/A	ENSP00000501898.1	A0A6Q8PFP0
	ENSG00000285901	ENST00000648100.1		n.*1967+6116T>C		intron	N/A	ENSP00000497536.1	A0A3B3IT44

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33034 AN: 151866 Hom.: 3885 Cov.: 31

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.217

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.217 AC: 33055 AN: 151982 Hom.: 3892 Cov.: 31 AF XY: 0.220 AC XY: 16321 AN XY: 74252

African (AFR) AF: 0.124 AC: 5163 AN: 41486

American (AMR) AF: 0.272 AC: 4156 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 529 AN: 3470

East Asian (EAS) AF: 0.247 AC: 1275 AN: 5164

South Asian (SAS) AF: 0.343 AC: 1652 AN: 4810

European-Finnish (FIN) AF: 0.270 AC: 2838 AN: 10510

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.247 AC: 16782 AN: 67960

Other (OTH) AF: 0.214 AC: 451 AN: 2104

Alfa AF: 0.215 Hom.: 1741

Bravo AF: 0.210

Asia WGS AF: 0.280 AC: 977 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
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.6
DANN	Benign	0.64
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs11063118; hg19: chr12-4481564;