rs121918498

Variant names:

• chr10-121520162-CG-AA
• rs121918498
• NM_022970.4:c.755_756delCGinsTT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM5 PP2 PP3 PP5_Moderate

The NM_022970.4(FGFR2):​c.755_756delCGinsTT​(p.Ser252Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S252L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR2 NM_022970.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 9.99
• Publications: 25 publications found

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 Gene-Disease associations (from GenCC):

• Apert syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• Beare-Stevenson cutis gyrata syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Genomics England PanelApp
• Crouzon syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, PanelApp Australia, Genomics England PanelApp, G2P
• Jackson-Weiss syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• LADD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Pfeiffer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
• bent bone dysplasia syndrome 1

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• familial scaphocephaly syndrome, McGillivray type

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• Saethre-Chotzen syndrome

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
• Antley-Bixler syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LADD syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_022970.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-121520163-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the FGFR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 2.402 (below the threshold of 3.09). Trascript score misZ: 4.3638 (above the threshold of 3.09). GenCC associations: The gene is linked to Pfeiffer syndrome type 3, Crouzon syndrome, Apert syndrome, Antley-Bixler syndrome, Beare-Stevenson cutis gyrata syndrome, Jackson-Weiss syndrome, bent bone dysplasia syndrome 1, Pfeiffer syndrome, Saethre-Chotzen syndrome, LADD syndrome 1, familial scaphocephaly syndrome, McGillivray type, LADD syndrome, Pfeiffer syndrome type 1, Pfeiffer syndrome type 2, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 10-121520162-CG-AA is Pathogenic according to our data. Variant chr10-121520162-CG-AA is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 13279.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_022970.4	c.755_756delCGinsTT	p.Ser252Phe	missense_variant		ENST00000457416.7	NP_075259.4
FGFR2	NM_000141.5	c.755_756delCGinsTT	p.Ser252Phe	missense_variant		ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000457416.7	c.755_756delCGinsTT	p.Ser252Phe	missense_variant		1	NM_022970.4	ENSP00000410294.2
FGFR2	ENST00000358487.10	c.755_756delCGinsTT	p.Ser252Phe	missense_variant		1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000369056.5	c.755_756delCGinsTT	p.Ser252Phe	missense_variant		1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.755_756delCGinsTT	p.Ser252Phe	missense_variant		1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.488_489delCGinsTT	p.Ser163Phe	missense_variant		5		ENSP00000484154.1
FGFR2	ENST00000369059.5	c.410_411delCGinsTT	p.Ser137Phe	missense_variant		5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.488_489delCGinsTT	p.Ser163Phe	missense_variant		2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.71_72delCGinsTT	p.Ser24Phe	missense_variant		1		ENSP00000474011.1
FGFR2	ENST00000604236.5	n.410_411delCGinsTT		non_coding_transcript_exon_variant	Exon 5 of 17	1		ENSP00000474109.1
FGFR2	ENST00000369061.8	c.749-4844_749-4843delCGinsTT		intron_variant	Intron 5 of 14	1		ENSP00000358057.4

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Acrocephalosyndactyly type I Pathogenic:2 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 17, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=0/100	disease causing

Splicing

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

Other links and lift over

dbSNP: rs121918498; hg19: chr10-123279676;