rs2304000

Positions:

• chr8-38429293-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_023110.3(FGFR1):​c.358+389G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 532,752 control chromosomes in the GnomAD database, including 11,540 homozygotes. 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: 𝑓 0.20 (3399 hom., cov: 33)
  • Exomes 𝑓: 0.20 (8141 hom.)
• Consequence: FGFR1 NM_023110.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0140

Genes affected

FGFR1 (HGNC:3688): (fibroblast growth factor receptor 1) The protein encoded by this gene is a member of the fibroblast growth factor receptor (FGFR) family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds both acidic and basic fibroblast growth factors and is involved in limb induction. Mutations in this gene have been associated with Pfeiffer syndrome, Jackson-Weiss syndrome, Antley-Bixler syndrome, osteoglophonic dysplasia, and autosomal dominant Kallmann syndrome 2. Chromosomal aberrations involving this gene are associated with stem cell myeloproliferative disorder and stem cell leukemia lymphoma syndrome. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.358+389G>C		intron_variant		ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.358+389G>C		intron_variant		1	NM_023110.3	ENSP00000400162	P4

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30968 AN: 152048 Hom.: 3380 Cov.: 33

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.0991

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.211

GnomAD3 exomes AF: 0.204 AC: 44108 AN: 215888 Hom.: 4652 AF XY: 0.199 AC XY: 23255 AN XY: 117050

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.231

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.314

Gnomad SAS exome AF: 0.104

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.221

Gnomad OTH exome AF: 0.203

GnomAD4 exome AF: 0.202 AC: 76760 AN: 380586 Hom.: 8141 Cov.: 0 AF XY: 0.194 AC XY: 41903 AN XY: 215652

Gnomad4 AFR exome AF: 0.162

Gnomad4 AMR exome AF: 0.231

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.319

Gnomad4 SAS exome AF: 0.109

Gnomad4 FIN exome AF: 0.180

Gnomad4 NFE exome AF: 0.225

Gnomad4 OTH exome AF: 0.210

GnomAD4 genome AF: 0.204 AC: 31035 AN: 152166 Hom.: 3399 Cov.: 33 AF XY: 0.199 AC XY: 14824 AN XY: 74378

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.226

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.310

Gnomad4 SAS AF: 0.0992

Gnomad4 FIN AF: 0.187

Gnomad4 NFE AF: 0.228

Gnomad4 OTH AF: 0.210

Alfa AF: 0.199 Hom.: 572

Bravo AF: 0.212

Asia WGS AF: 0.202 AC: 703 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.9
DANN	Benign	0.57

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: rs2304000; hg19: chr8-38286811; COSMIC: COSV58328363; COSMIC: COSV58328363;