4-1806195-G-A

Position:

• chr4-1806195-G-A

Variant summary

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

The NM_000142.5(FGFR3):​c.1959+22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,611,346 control chromosomes in the GnomAD database, including 571 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (59 hom., cov: 34)
  • Exomes 𝑓: 0.020 (512 hom.)
• Consequence: FGFR3 NM_000142.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.23

Genes affected

FGFR3 (HGNC:3690): (fibroblast growth factor receptor 3) This gene encodes a member of the fibroblast growth factor receptor (FGFR) family, with its amino acid sequence being highly conserved between members and among divergent species. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist 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 acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance. Mutations in this gene lead to craniosynostosis and multiple types of skeletal dysplasia. [provided by RefSeq, Aug 2017]

FGFR3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-1806195-G-A is Benign according to our data. Variant chr4-1806195-G-A is described in ClinVar as [Benign]. Clinvar id is 255335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1806195-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR3	NM_000142.5	c.1959+22G>A		intron_variant		ENST00000440486.8	NP_000133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8	c.1959+22G>A		intron_variant		5	NM_000142.5	ENSP00000414914.2

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2861 AN: 152208 Hom.: 58 Cov.: 34

Gnomad AFR AF: 0.00439

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0649

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0472

Gnomad FIN AF: 0.00885

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.0253

GnomAD3 exomes AF: 0.0307 AC: 7603 AN: 248012 Hom.: 227 AF XY: 0.0301 AC XY: 4061 AN XY: 134778

Gnomad AFR exome AF: 0.00347

Gnomad AMR exome AF: 0.0949

Gnomad ASJ exome AF: 0.0421

Gnomad EAS exome AF: 0.000273

Gnomad SAS exome AF: 0.0486

Gnomad FIN exome AF: 0.00945

Gnomad NFE exome AF: 0.0181

Gnomad OTH exome AF: 0.0266

GnomAD4 exome AF: 0.0198 AC: 28862 AN: 1459020 Hom.: 512 Cov.: 38 AF XY: 0.0206 AC XY: 14959 AN XY: 725816

Gnomad4 AFR exome AF: 0.00281

Gnomad4 AMR exome AF: 0.0909

Gnomad4 ASJ exome AF: 0.0423

Gnomad4 EAS exome AF: 0.000555

Gnomad4 SAS exome AF: 0.0509

Gnomad4 FIN exome AF: 0.0110

Gnomad4 NFE exome AF: 0.0155

Gnomad4 OTH exome AF: 0.0206

GnomAD4 genome AF: 0.0188 AC: 2866 AN: 152326 Hom.: 59 Cov.: 34 AF XY: 0.0202 AC XY: 1503 AN XY: 74476

Gnomad4 AFR AF: 0.00438

Gnomad4 AMR AF: 0.0653

Gnomad4 ASJ AF: 0.0441

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0470

Gnomad4 FIN AF: 0.00885

Gnomad4 NFE AF: 0.0162

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0211 Hom.: 7

Bravo AF: 0.0231

Asia WGS AF: 0.0210 AC: 74 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.0
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3135898; hg19: chr4-1807922; COSMIC: COSV53415329; COSMIC: COSV53415329;