10-121517379-A-G

Position:

• chr10-121517379-A-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000141.5(FGFR2):​c.1024T>C​(p.Cys342Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C342F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 9.26

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 Pathogenic. Variant got 19 ACMG points.

• PM1: In a strand (size 8) in uniprot entity FGFR2_HUMAN there are 20 pathogenic changes around while only 0 benign (100%) in NM_000141.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-121517378-C-A is described in Lovd as [Pathogenic].
• 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, 0.993
• PP5: Variant 10-121517379-A-G is Pathogenic according to our data. Variant chr10-121517379-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121517379-A-G is described in Lovd as [Pathogenic]. Variant chr10-121517379-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1024T>C	p.Cys342Arg	missense_variant	8/18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1024T>C	p.Cys342Arg	missense_variant	8/18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000613048.4	c.757T>C	p.Cys253Arg	missense_variant	7/17	5		ENSP00000484154.1
FGFR2	ENST00000478859.5	c.340T>C	p.Cys114Arg	missense_variant	7/17	1		ENSP00000474011.1
FGFR2	ENST00000457416.7	c.1087+1303T>C		intron_variant		1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1087+1303T>C		intron_variant		1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1087+1303T>C		intron_variant		1		ENSP00000358054.3
FGFR2	ENST00000369061.8	c.749-2060T>C		intron_variant		1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.742+1303T>C		intron_variant		5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.820+1303T>C		intron_variant		2		ENSP00000353262.3
FGFR2	ENST00000604236.5	n.*71T>C		non_coding_transcript_exon_variant	7/17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*71T>C		3_prime_UTR_variant	7/17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pfeiffer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 17, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 27, 2019	This previously reported FGFR2 variant (rs121918488) is absent from large population datasets. Two submitters in ClinVar classify this variant as pathogenic. Multiple different missense changes have been reported in the same residue that have been shown to affect protein functionality. Two bioinformatic tools queried predict that the substitution would be possibly damaging, but these algorithms have low specificity, especially for predicting gain of function variants. This variant is considered pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2000	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23754559, 9385368, 28901406, 8528214, 25759925, 7987400, 7719345, 25517871, 11343324, 8755573, 16418739, 11173845, 31837199, 12884424, 27228464, 24127277, 28600064, 29436723, 10633130, 10712195, 24656465, 10394936, 24411056, 27596331) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

FGFR2-related craniosynostosis Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 342 of the FGFR2 protein (p.Cys342Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Crouzon or Pfeiffer syndromes (PMID: 7987400, 12884424, 24127277, 25759925). ClinVar contains an entry for this variant (Variation ID: 13266). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FGFR2 protein function with a positive predictive value of 95%. This variant disrupts the p.Cys342 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24127277). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -

Crouzon syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PM5+PP3_Strong+PP2+PS2_Moderate+PS4+PP4 -

Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -

Jackson-Weiss syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;.;D;.;.;.;D;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	.;.;H;.;.;H;.;.
PROVEAN	Pathogenic	-9.2	D;.;D;.;D;D;.;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0060	D;.;D;.;D;D;.;D
Sift4G	Uncertain	0.013	D;D;D;D;D;D;D;.
Polyphen		0.97	D;.;.;.;P;.;.;.
Vest4		0.99
MutPred		0.98		.;.;Gain of methylation at C342 (P = 0.043);.;.;Gain of methylation at C342 (P = 0.043);.;.;
MVP		0.96
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs121918488; hg19: chr10-123276893;