rs3135868

Positions:

• chr4-1799815-A-G

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.445+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0228 in 1,612,658 control chromosomes in the GnomAD database, including 3,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (1986 hom., cov: 33)
  • Exomes 𝑓: 0.015 (1853 hom.)
• Consequence: FGFR3 NM_000142.5 splice_donor_region, intron
• Scores: Splicing: ADA: 0.009277
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.14

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-1799815-A-G is Benign according to our data. Variant chr4-1799815-A-G is described in ClinVar as [Benign]. Clinvar id is 255341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1799815-A-G is described in Lovd as [Benign]. Variant chr4-1799815-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR3	NM_000142.5	c.445+3A>G		splice_donor_region_variant, intron_variant		ENST00000440486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR3	ENST00000440486.8	c.445+3A>G		splice_donor_region_variant, intron_variant		5	NM_000142.5	P4

Frequencies

GnomAD3 genomes AF: 0.0927 AC: 14096 AN: 152110 Hom.: 1967 Cov.: 33

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0391

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.0254

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00676

Gnomad OTH AF: 0.0731

GnomAD3 exomes AF: 0.0310 AC: 7708 AN: 248904 Hom.: 798 AF XY: 0.0255 AC XY: 3451 AN XY: 135116

Gnomad AFR exome AF: 0.306

Gnomad AMR exome AF: 0.0204

Gnomad ASJ exome AF: 0.0265

Gnomad EAS exome AF: 0.0226

Gnomad SAS exome AF: 0.0163

Gnomad FIN exome AF: 0.000373

Gnomad NFE exome AF: 0.00717

Gnomad OTH exome AF: 0.0224

GnomAD4 exome AF: 0.0154 AC: 22544 AN: 1460430 Hom.: 1853 Cov.: 33 AF XY: 0.0148 AC XY: 10731 AN XY: 726514

Gnomad4 AFR exome AF: 0.312

Gnomad4 AMR exome AF: 0.0222

Gnomad4 ASJ exome AF: 0.0285

Gnomad4 EAS exome AF: 0.0266

Gnomad4 SAS exome AF: 0.0181

Gnomad4 FIN exome AF: 0.000612

Gnomad4 NFE exome AF: 0.00495

Gnomad4 OTH exome AF: 0.0317

GnomAD4 genome AF: 0.0930 AC: 14164 AN: 152228 Hom.: 1986 Cov.: 33 AF XY: 0.0891 AC XY: 6636 AN XY: 74444

Gnomad4 AFR AF: 0.304

Gnomad4 AMR AF: 0.0391

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.0255

Gnomad4 SAS AF: 0.0155

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00675

Gnomad4 OTH AF: 0.0733

Alfa AF: 0.0486 Hom.: 470

Bravo AF: 0.105

Asia WGS AF: 0.0600 AC: 207 AN: 3476

EpiCase AF: 0.00894

EpiControl AF: 0.0104

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2016	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. -

not provided Benign:3

Likely 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	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	14
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0093
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: -15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3135868; hg19: chr4-1801542; COSMIC: COSV53409724; COSMIC: COSV53409724;