10-121517316-T-C

Position:

• chr10-121517316-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_000141.5(FGFR2):​c.1084+3A>G variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR2 NM_000141.5 splice_region, intron
• Scores: Splicing: ADA: 0.2476
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.96

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-121517316-T-C is Pathogenic according to our data. Variant chr10-121517316-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121517316-T-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.18). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1084+3A>G		splice_region_variant, intron_variant		ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1084+3A>G		splice_region_variant, intron_variant		1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.1087+1366A>G		intron_variant		1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1087+1366A>G		intron_variant		1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1087+1366A>G		intron_variant		1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.817+3A>G		splice_region_variant, intron_variant		5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.749-1997A>G		intron_variant		1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.742+1366A>G		intron_variant		5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.820+1366A>G		intron_variant		2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.400+3A>G		splice_region_variant, intron_variant		1		ENSP00000474011.1
FGFR2	ENST00000604236.5	n.*131+3A>G		splice_region_variant, intron_variant		1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pfeiffer syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 15, 2016	- -

FGFR2-related craniosynostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 25, 2022

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 15286168). This sequence change falls in intron 8 of the FGFR2 gene. It does not directly change the encoded amino acid sequence of the FGFR2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Crouzon syndrome and/or Pfeiffer syndrome (PMID: 10394936, 15286168). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13299). -

Crouzon syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2004

- -

Acrocephalosyndactyly type I;C0010273:Crouzon syndrome;C0220658:Pfeiffer syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Clinical Genomics Laboratory, Stanford Medicine

Mar 03, 2020

The c.1084+3A>G variant (also described as NM_022970.3:c.1087+1366A>G) in the FGFR2 gene has been previously reported in two unrelated individuals with Crouzon syndrome and one individual with Pfeiffer syndrome (Cornejo-Roldan et al., 1999; Roscioli et al., 2013; Apra et al., 2016). Additionally, this variant co-segregated with disease in four affected relatives from one family. Only one of the affected family members had a known history of craniosynostosis while the remaining three had characteristic facial features including exorbitism (Kan et al., 2004). The c.1084+3A>G variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The c.1084+3A>G variant is thought to activate a cryptic splice site and functional studies of this variant show aberrant splicing with two abnormal splice products present in patient cells (Kan et al., 2004). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.1084+3A>G variant as likely pathogenic for FGFR2-related craniosynostosis in an autosomal dominant manner based on the information above. [ACMG evidence codes used: PS2_Strong; PM2; PM4; PP1_Supporting] -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 11, 2022

Published functional studies demonstrate this variant leads to activation of an upstream cryptic donor splice site resulting in an in-frame variant (Kan et al., 2004); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 10394936, 24127277, 15286168) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Benign	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.25
dbscSNV1_RF	Benign	0.48
SpliceAI score (max)		0.020		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: rs879253721; hg19: chr10-123276830;