rs879253720

Variant names:

• chr10-121488027-ATCT-A
• rs879253720
• NM_000141.5:c.1947_1949delAGA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_000141.5(FGFR2):​c.1947_1949delAGA​(p.Arg649_Asp650delinsSer) variant causes a disruptive inframe deletion 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR2 NM_000141.5 disruptive_inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.98
• Publications: 0 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 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000141.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000141.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 10-121488027-ATCT-A is Pathogenic according to our data. Variant chr10-121488027-ATCT-A is described in ClinVar as [Pathogenic]. Clinvar id is 13297.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1947_1949delAGA	p.Arg649_Asp650delinsSer	disruptive_inframe_deletion	Exon 14 of 18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1947_1949delAGA	p.Arg649_Asp650delinsSer	disruptive_inframe_deletion	Exon 14 of 18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.1950_1952delAGA	p.Arg650_Asp651delinsSer	disruptive_inframe_deletion	Exon 14 of 18	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1950_1952delAGA	p.Arg650_Asp651delinsSer	disruptive_inframe_deletion	Exon 13 of 17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1950_1952delAGA	p.Arg650_Asp651delinsSer	disruptive_inframe_deletion	Exon 14 of 17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.1680_1682delAGA	p.Arg560_Asp561delinsSer	disruptive_inframe_deletion	Exon 13 of 17	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.1611_1613delAGA	p.Arg537_Asp538delinsSer	disruptive_inframe_deletion	Exon 11 of 15	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.1605_1607delAGA	p.Arg535_Asp536delinsSer	disruptive_inframe_deletion	Exon 12 of 16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.1683_1685delAGA	p.Arg561_Asp562delinsSer	disruptive_inframe_deletion	Exon 13 of 17	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.1263_1265delAGA	p.Arg421_Asp422delinsSer	disruptive_inframe_deletion	Exon 13 of 17	1		ENSP00000474011.1
FGFR2	ENST00000429361.5	c.723_725delAGA	p.Arg241_Asp242delinsSer	disruptive_inframe_deletion	Exon 6 of 9	5		ENSP00000404219.1
FGFR2	ENST00000604236.5	n.*994_*996delAGA		non_coding_transcript_exon_variant	Exon 13 of 17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*994_*996delAGA		3_prime_UTR_variant	Exon 13 of 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: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Levy-Hollister syndrome Pathogenic:1

Apr 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs879253720; hg19: chr10-123247541;