rs1554928786

chr10-121517318-C-CTGTTGA

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000141.5(FGFR2):c.1084_1084+1insTCAACA(p.Ala362delinsValAsnThr) variant causes a protein altering, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A362A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR2 NM_000141.5 protein_altering, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85

Genes affected

FGFR2 (HGNC:3689): (fibroblast growth factor receptor 2) The protein encoded by this gene is a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists 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 is a high-affinity receptor for acidic, basic and/or keratinocyte growth factor, depending on the isoform. Mutations in this gene are associated with Crouzon syndrome, Pfeiffer syndrome, Craniosynostosis, Apert syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata syndrome, Saethre-Chotzen syndrome, and syndromic craniosynostosis. Multiple alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jan 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR2	NM_000141.5	c.1084_1084+1insTCAACA	p.Ala362delinsValAsnThr	protein_altering_variant, splice_region_variant		ENST00000358487.10
FGFR2	NM_022970.4	c.1087+1363_1087+1364insTCAACA		intron_variant		ENST00000457416.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR2	ENST00000358487.10	c.1084_1084+1insTCAACA	p.Ala362delinsValAsnThr	protein_altering_variant, splice_region_variant		1	NM_000141.5	A2
FGFR2	ENST00000457416.7	c.1087+1363_1087+1364insTCAACA		intron_variant		1	NM_022970.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

FGFR2-related craniosynostosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2017

This sequence change inserts 6 nucleotides at the exon 8 / intron 8 junction of the FGFR2 gene (c.1084_1084+1insTCAACA). This disrupts the sequence that constitute the consensus donor 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. Experimental studies have shown that this insertion inactivates the consensus donor splice site and subsequently activates a cryptic splice site.  Use of this cryptic splice site causes a deletion of 17 amino acids and moves the third immunoglobulin-like domain closer to the transmembrane domain of the resulting FGFR2 protein. However, the functional consequence of the loss of these 17 amino acids on FGFR2 protein function has not been reported (PMID: 8644708). This variant has been reported to segregate with Pfieffer syndrome in a single family (PMID: 8644708). This variant has also been reported as c.1263insTCAACA. This variant is not present in population databases (ExAC no frequency). -

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: rs1554928786; hg19: chr10-123276832;