rs2305183

chr4-1801580-T-Cchr4-1801580-T-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.616-40T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,583,716 control chromosomes in the GnomAD database, including 23,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4667 hom., cov: 34)
  • Exomes 𝑓: 0.15 (18474 hom.)
• Consequence: FGFR3 NM_000142.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.892

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=-0.93).
• BP6: Variant 4-1801580-T-C is Benign according to our data. Variant chr4-1801580-T-C is described in ClinVar as [Benign]. Clinvar id is 255343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1801580-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR3	NM_000142.5	c.616-40T>C		intron_variant		ENST00000440486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR3	ENST00000440486.8	c.616-40T>C		intron_variant		5	NM_000142.5	P4

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32612 AN: 152088 Hom.: 4637 Cov.: 34

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.0662

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.209

GnomAD3 exomes AF: 0.160 AC: 31080 AN: 193970 Hom.: 3100 AF XY: 0.160 AC XY: 16956 AN XY: 105956

Gnomad AFR exome AF: 0.403

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.217

Gnomad EAS exome AF: 0.0425

Gnomad SAS exome AF: 0.212

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.152 AC: 217972 AN: 1431510 Hom.: 18474 Cov.: 39 AF XY: 0.154 AC XY: 109056 AN XY: 709838

Gnomad4 AFR exome AF: 0.417

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.224

Gnomad4 EAS exome AF: 0.0942

Gnomad4 SAS exome AF: 0.212

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.171

GnomAD4 genome AF: 0.215 AC: 32699 AN: 152206 Hom.: 4667 Cov.: 34 AF XY: 0.211 AC XY: 15722 AN XY: 74434

Gnomad4 AFR AF: 0.404

Gnomad4 AMR AF: 0.147

Gnomad4 ASJ AF: 0.213

Gnomad4 EAS AF: 0.0664

Gnomad4 SAS AF: 0.203

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.209

Alfa AF: 0.125 Hom.: 292

Bravo AF: 0.226

Asia WGS AF: 0.181 AC: 629 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.39
Dann	Benign	0.12
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: rs2305183; hg19: chr4-1803307; COSMIC: COSV53402151; COSMIC: COSV53402151;