chr10-121520162-CG-AA

Variant names:

• chr10-121520162-CG-AA
• rs121918498
• NM_000141.5:c.755_756delCGinsTT

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_Moderate PM2 PM5 PP2 PP3 PP5_Moderate

The NM_000141.5(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. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S252L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 9.99

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 Pathogenic. Variant got 10 ACMG points.

• PS1: Transcript NM_000141.5 (FGFR2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-121520163-G-A is described in Lovd as [Pathogenic].
• 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: 4.4365 (above the threshold of 3.09). GenCC associations: The gene is linked to Pfeiffer syndrome type 3, Antley-Bixler syndrome, Pfeiffer syndrome type 2, Saethre-Chotzen syndrome, Beare-Stevenson cutis gyrata syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Pfeiffer syndrome type 1, LADD syndrome 1, Pfeiffer syndrome, bent bone dysplasia syndrome 1, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis, familial scaphocephaly syndrome, McGillivray type, Apert syndrome, LADD syndrome.
• 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 id 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_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	ENST00000358487.10	c.755_756delCGinsTT	p.Ser252Phe	missense_variant		1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.755_756delCGinsTT	p.Ser252Phe	missense_variant		1		ENSP00000410294.2
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	ENST00000369061.8	c.749-4844_749-4843delCGinsTT		intron_variant	Intron 5 of 14	1		ENSP00000358057.4
FGFR2	ENST00000604236.5	n.410_411delCGinsTT		non_coding_transcript_exon_variant	Exon 5 of 17	1		ENSP00000474109.1

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

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

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Mar 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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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: rs121918498; hg19: chr10-123279676;