4-1793812-GCTGCCTTC-G

Position:

• chr4-1793812-GCTGCCTTC-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000142.5(FGFR3):​c.-102-18_-102-11del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00677 in 177,748 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0060 (8 hom., cov: 32)
  • Exomes 𝑓: 0.011 (0 hom.)
• Consequence: FGFR3 NM_000142.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.849

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 -10 ACMG points.

• BP6: Variant 4-1793812-GCTGCCTTC-G is Benign according to our data. Variant chr4-1793812-GCTGCCTTC-G is described in ClinVar as [Benign]. Clinvar id is 1229898.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-1793812-GCTGCCTTC-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00595 (886/148874) while in subpopulation NFE AF= 0.00873 (581/66554). AF 95% confidence interval is 0.00814. There are 8 homozygotes in gnomad4. There are 416 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR3	NM_000142.5	c.-102-18_-102-11del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000440486.8	NP_000133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8	c.-102-18_-102-11del		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000142.5	ENSP00000414914	P4

Frequencies

GnomAD3 genomes AF: 0.00595 AC: 885 AN: 148766 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00168

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.00593

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00696

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00873

Gnomad OTH AF: 0.00877

GnomAD4 exome AF: 0.0110 AC: 317 AN: 28874 Hom.: 0 AF XY: 0.0112 AC XY: 175 AN XY: 15572

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00326

Gnomad4 ASJ exome AF: 0.00957

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0101

Gnomad4 NFE exome AF: 0.0125

Gnomad4 OTH exome AF: 0.00875

GnomAD4 genome AF: 0.00595 AC: 886 AN: 148874 Hom.: 8 Cov.: 32 AF XY: 0.00573 AC XY: 416 AN XY: 72582

Gnomad4 AFR AF: 0.00168

Gnomad4 AMR AF: 0.00592

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00696

Gnomad4 NFE AF: 0.00873

Gnomad4 OTH AF: 0.00868

Alfa AF: 0.00778 Hom.: 2

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

Nov 13, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1452696194; hg19: chr4-1795539;