rs121918507

Positions:

• chr10-121498591-T-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The ENST00000358487.10(FGFR2):​c.1576A>G​(p.Lys526Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR2 ENST00000358487.10 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.01

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 15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in ENST00000358487.10
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FGFR2. . Gene score misZ 2.402 (greater than the threshold 3.09). Trascript score misZ 4.4365 (greater than threshold 3.09). GenCC has associacion of gene with 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: MetaRNN computational evidence supports a deleterious effect, 0.876
• PP5: Variant 10-121498591-T-C is Pathogenic according to our data. Variant chr10-121498591-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_022970.4	c.1579A>G	p.Lys527Glu	missense_variant	12/18	ENST00000457416.7	NP_075259.4
FGFR2	NM_000141.5	c.1576A>G	p.Lys526Glu	missense_variant	12/18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000457416.7	c.1579A>G	p.Lys527Glu	missense_variant	12/18	1	NM_022970.4	ENSP00000410294	P4
FGFR2	ENST00000358487.10	c.1576A>G	p.Lys526Glu	missense_variant	12/18	1	NM_000141.5	ENSP00000351276	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Crouzon syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2005

- -

Familial scaphocephaly syndrome, McGillivray type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2005

- -

Pfeiffer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 25, 2024

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 01, 2024

Published functional studies demonstrate a damaging effect: increased activation of the FGFR2 kinase (PMID: 17803937); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16061565, 17803937, 15523492) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;.;.;D;.;.;.;D;D;.;T;.;.;.;.;.
Eigen	Benign	-0.10
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.00020	T
MutationAssessor	Benign	0.19	.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.4	D;D;.;D;.;D;D;D;D;D;.;D;D;D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	D;D;.;D;.;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Benign	0.080	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.12, 0.73, 0.071, 0.0020, 0.68	.;B;.;P;.;B;.;.;.;.;.;.;B;P;.;.
Vest4		0.79
MutPred		0.76		.;.;.;Loss of ubiquitination at K526 (P = 0.0087);.;.;.;.;.;.;Loss of ubiquitination at K526 (P = 0.0087);.;.;.;.;.;
MVP		0.94
MPC		2.1
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.95
gMVP		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs121918507; hg19: chr10-123258105;