rs387906677

Positions:

• chr10-121515232-A-C
• chr10-121515232-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_000141.5(FGFR2):​c.1172T>G​(p.Met391Arg) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.23

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 Likely_pathogenic. Variant got 6 ACMG points.

• 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, 0.836
• PP5: Variant 10-121515232-A-C is Pathogenic according to our data. Variant chr10-121515232-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 29855.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_022970.4	c.1175T>G	p.Met392Arg	missense_variant	9/18	ENST00000457416.7	NP_075259.4
FGFR2	NM_000141.5	c.1172T>G	p.Met391Arg	missense_variant	9/18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000457416.7	c.1175T>G	p.Met392Arg	missense_variant	9/18	1	NM_022970.4	ENSP00000410294	P4
FGFR2	ENST00000358487.10	c.1172T>G	p.Met391Arg	missense_variant	9/18	1	NM_000141.5	ENSP00000351276	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Bent bone dysplasia syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 09, 2012

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 14, 2015

The M391R variant in the FGFR2 gene has been reported previously in the heterozygous state and presumed de novo in three unrelated fetuses described to have a perinatal lethal skeletal dysplasia called bent bone dysplasia syndrome (Merrill et al., 2012). Features in these fetuses included craniosyostosis, poorly mineralized calvarium, dysmorphic facial features, prenatal teeth, hypoplastic pubis and clavicles, osteopenia, and bent long bones (Merrill et al., 2012). Functional studies of the M391R substitutiondetermined it results in reduction of plasma membrane levels of FGFR2, thus diminishing receptor responsiveness to extracellular fibroblast growth factors (Merrill et al., 2012). Further studies of M391R revealed enhanced nuclear FGFR2 activity, with direct interaction with ribosomal RNA, ultimately promoting proliferation and reducing osteoblast differentiation in osteoprogenitor cells (Neben et al., 2014). The M391R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M391R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the transmembrane domain that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret M391R as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	30
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.81	.;.;.;D;.;.;T;.;T;.;.;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.7	.;.;.;M;.;.;.;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.5	N;D;.;D;.;D;D;D;.;D;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0080	D;D;.;D;.;D;D;D;.;D;D;D;D;D
Sift4G	Benign	0.10	T;T;T;T;T;T;T;T;T;D;T;D;D;.
Polyphen		0.96, 0.84, 0.59, 0.38, 0.96	.;D;.;P;.;P;.;.;.;.;B;D;.;.
Vest4		0.92
MutPred		0.69		.;.;.;Gain of MoRF binding (P = 0.0141);.;.;.;Gain of MoRF binding (P = 0.0141);.;.;.;.;.;.;
MVP		0.92
MPC		2.2
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.89
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906677; hg19: chr10-123274746; COSMIC: COSV60651291; COSMIC: COSV60651291;