4-1793606-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000142.5(FGFR3):c.-103+141C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 149,536 control chromosomes in the GnomAD database, including 1,690 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.14 (1680 hom., cov: 31)
  • Exomes 𝑓: 0.16 (10 hom.)
• Consequence: FGFR3 NM_000142.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.508

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 4-1793606-C-T is Benign according to our data. Variant chr4-1793606-C-T is described in ClinVar as [Benign]. Clinvar id is 1251273.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR3	NM_000142.5	c.-103+141C>T		intron_variant		ENST00000440486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR3	ENST00000440486.8	c.-103+141C>T		intron_variant		5	NM_000142.5	P4

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20421 AN: 148772 Hom.: 1679 Cov.: 31

Gnomad AFR AF: 0.0538

Gnomad AMI AF: 0.0973

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.0256

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.167

GnomAD4 exome AF: 0.161 AC: 106 AN: 658 Hom.: 10 AF XY: 0.154 AC XY: 74 AN XY: 482

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0625

Gnomad4 ASJ exome AF: 0.300

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.150

Gnomad4 FIN exome AF: 0.206

Gnomad4 NFE exome AF: 0.165

Gnomad4 OTH exome AF: 0.233

GnomAD4 genome AF: 0.137 AC: 20421 AN: 148878 Hom.: 1680 Cov.: 31 AF XY: 0.138 AC XY: 10051 AN XY: 72664

Gnomad4 AFR AF: 0.0538

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.261

Gnomad4 EAS AF: 0.0257

Gnomad4 SAS AF: 0.201

Gnomad4 FIN AF: 0.192

Gnomad4 NFE AF: 0.176

Gnomad4 OTH AF: 0.166

Alfa AF: 0.0788 Hom.: 107

Bravo AF: 0.130

Asia WGS AF: 0.110 AC: 352 AN: 3224

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	18
Dann	Uncertain	0.98

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: rs17879199; hg19: chr4-1795333; COSMIC: COSV53421799; COSMIC: COSV53421799;