rs756854039

Positions:

• chr4-1799810-CAGGT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP3_Moderate

The NM_000142.5(FGFR3):​c.445+2_445+5del variant causes a splice donor, coding sequence change. The variant allele was found at a frequency of 0.0000732 in 1,612,758 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: FGFR3 NM_000142.5 splice_donor, coding_sequence
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.30

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.02684841 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.3, offset of -12, new splice context is: cagGTgtgg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR3	NM_000142.5	c.445+2_445+5del		splice_donor_variant, coding_sequence_variant	4/18	ENST00000440486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR3	ENST00000440486.8	c.445+2_445+5del		splice_donor_variant, coding_sequence_variant	4/18	5	NM_000142.5	P4

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000562 AC: 14 AN: 249012 Hom.: 0 AF XY: 0.0000814 AC XY: 11 AN XY: 135174

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000624

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000726 AC: 106 AN: 1460494 Hom.: 0 AF XY: 0.0000867 AC XY: 63 AN XY: 726550

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000684

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74450

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000680

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 11, 2023	This sequence change affects a splice site in intron 4 of the FGFR3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in FGFR3 cause disease. This variant is present in population databases (rs756854039, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with clinical features of FGFR3-related conditions (PMID: 28252636). ClinVar contains an entry for this variant (Variation ID: 533894). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2023	Identified along with a variant in the ARID1B gene in a patient with Coffin-Siris syndrome in published literature (Baldridge et al., 2017); Canonical splice site variant in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; This variant is associated with the following publications: (PMID: 28252636, 34308104) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 15, 2023	- -

Camptodactyly-tall stature-scoliosis-hearing loss syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Aug 09, 2022

The c.444_445+2delAGGT variant is not present in publicly available population databases like 1000 Genomes or in our in-house exome database.. The variant is present in EVS, ExAC, gnomAD and Indian Exome Database at low frequency. The variant is located at the exon 4-intron 4 splice junction and is expected to affect splicing. Similar splice-site variant at the intron 4 (NM_000142.4:c.445+2_445+5delTAGG) has been previously observed in a patient with FGFR3-related conditions (PMID: 28252636) and reported to ClinVar (Accession ID: VCV000533894.5) as ‘variant of uncertain significance’. In-silico pathogenicity prediction programs like MutationTaster2, CADD. Varsome, Franklin etc. predicted this variant to be likely deleterious. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant disrupts the consensus splice site, however these predictions were not confirmed by any published functional studies. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: -10
DS_DL_spliceai		0.99		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs756854039; hg19: chr4-1801537;