12-4368914-T-A

Position:

• chr12-4368914-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020638.3(FGF23):​c.*1429A>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 0.231 in 221,966 control chromosomes in the GnomAD database, including 6,476 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4401 hom., cov: 31)
  • Exomes 𝑓: 0.24 (2075 hom.)
• Consequence: FGF23 NM_020638.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.305

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-4368914-T-A is Benign according to our data. Variant chr12-4368914-T-A is described in ClinVar as [Benign]. Clinvar id is 308779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGF23	NM_020638.3	c.*1429A>T		3_prime_UTR_variant	3/3	ENST00000237837.2	NP_065689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGF23	ENST00000237837.2	c.*1429A>T		3_prime_UTR_variant	3/3	1	NM_020638.3	ENSP00000237837	P1

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34613 AN: 151746 Hom.: 4399 Cov.: 31

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.236

GnomAD4 exome AF: 0.237 AC: 16580 AN: 70102 Hom.: 2075 Cov.: 0 AF XY: 0.235 AC XY: 7614 AN XY: 32370

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.269

Gnomad4 ASJ exome AF: 0.259

Gnomad4 EAS exome AF: 0.132

Gnomad4 SAS exome AF: 0.164

Gnomad4 FIN exome AF: 0.292

Gnomad4 NFE exome AF: 0.267

Gnomad4 OTH exome AF: 0.244

GnomAD4 genome AF: 0.228 AC: 34613 AN: 151864 Hom.: 4401 Cov.: 31 AF XY: 0.230 AC XY: 17070 AN XY: 74194

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.260

Gnomad4 EAS AF: 0.205

Gnomad4 SAS AF: 0.174

Gnomad4 FIN AF: 0.335

Gnomad4 NFE AF: 0.273

Gnomad4 OTH AF: 0.233

Alfa AF: 0.113 Hom.: 235

Bravo AF: 0.219

Asia WGS AF: 0.191 AC: 662 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal dominant hypophosphatemic rickets Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Tumoral calcinosis, hyperphosphatemic, familial, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.6
DANN	Benign	0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs11063112; hg19: chr12-4478080;