rs1554928978

Positions:

• chr10-121517424-GAACCTCAATCTCTTTGTCCGTGGTGTTAACACCGGCGGCCTAGAAAACAAGGGAAGCAAAAGAAAAGGCTAGACGACACAGGAATGATTGTGGAGGGGGCTGTGGAACCACAAGGCGTCGCACCGGGGGCTTCAGGGGGTGCTGGCCACTGGGAGATTCCGACTGCAGCCCATCCACAAAGCCCACAACCGAGAGACACGGAGC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000141.5(FGFR2):​c.940-165_978del​(p.Ala314_Leu327del) variant causes a splice acceptor, conservative inframe deletion, splice region, intron 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR2 NM_000141.5 splice_acceptor, conservative_inframe_deletion, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.26

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]

FGFR2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-121517424-GAACCTCAATCTCTTTGTCCGTGGTGTTAACACCGGCGGCCTAGAAAACAAGGGAAGCAAAAGAAAAGGCTAGACGACACAGGAATGATTGTGGAGGGGGCTGTGGAACCACAAGGCGTCGCACCGGGGGCTTCAGGGGGTGCTGGCCACTGGGAGATTCCGACTGCAGCCCATCCACAAAGCCCACAACCGAGAGACACGGAGC-G is Pathogenic according to our data. Variant chr10-121517424-GAACCTCAATCTCTTTGTCCGTGGTGTTAACACCGGCGGCCTAGAAAACAAGGGAAGCAAAAGAAAAGGCTAGACGACACAGGAATGATTGTGGAGGGGGCTGTGGAACCACAAGGCGTCGCACCGGGGGCTTCAGGGGGTGCTGGCCACTGGGAGATTCCGACTGCAGCCCATCCACAAAGCCCACAACCGAGAGACACGGAGC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520630.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.940-165_978del	p.Ala314_Leu327del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	8/18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.940-165_978del	p.Ala314_Leu327del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	8/18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.1087+1054_1087+1257del		intron_variant		1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1087+1054_1087+1257del		intron_variant		1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1087+1054_1087+1257del		intron_variant		1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.673-165_711del	p.Ala225_Leu238del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	7/17	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.749-2309_749-2106del		intron_variant		1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.742+1054_742+1257del		intron_variant		5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.820+1054_820+1257del		intron_variant		2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.256-165_294del	p.Ala86_Leu99del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	7/17	1		ENSP00000474011.1
FGFR2	ENST00000604236.5	n.743-165_*25del		splice_region_variant, non_coding_transcript_exon_variant	7/17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.743-165_*25del		splice_acceptor_variant, splice_region_variant, 3_prime_UTR_variant, intron_variant	7/17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2015

- -

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: rs1554928978; hg19: chr10-123276938;