chr10-121515254-C-T

Variant names:

• chr10-121515254-C-T
• rs1554927408
• NM_000141.5:c.1150G>A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000141.5(FGFR2):​c.1150G>A​(p.Gly384Arg) 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. 12/21 in silico tools predict a damaging 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, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.83

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.

• PM2: Very rare variant in population databases, with high coverage
• 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: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 10-121515254-C-T is Pathogenic according to our data. Variant chr10-121515254-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 478046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1150G>A	p.Gly384Arg	missense_variant	Exon 9 of 18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1150G>A	p.Gly384Arg	missense_variant	Exon 9 of 18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.1153G>A	p.Gly385Arg	missense_variant	Exon 9 of 18	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1153G>A	p.Gly385Arg	missense_variant	Exon 8 of 17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1153G>A	p.Gly385Arg	missense_variant	Exon 9 of 17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.883G>A	p.Gly295Arg	missense_variant	Exon 8 of 17	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.814G>A	p.Gly272Arg	missense_variant	Exon 6 of 15	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.808G>A	p.Gly270Arg	missense_variant	Exon 7 of 16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.886G>A	p.Gly296Arg	missense_variant	Exon 8 of 17	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.466G>A	p.Gly156Arg	missense_variant	Exon 8 of 17	1		ENSP00000474011.1
FGFR2	ENST00000604236.5	n.*197G>A		non_coding_transcript_exon_variant	Exon 8 of 17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*197G>A		3_prime_UTR_variant	Exon 8 of 17	1		ENSP00000474109.1
FGFR2	ENST00000429361.5	c.-75G>A		upstream_gene_variant		5		ENSP00000404219.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FGFR2-related craniosynostosis Pathogenic:1

Mar 31, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this is a rare missense variant that has been observed to be de novo in one affected individual and present in several other affected individuals. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 384 of the FGFR2 protein (p.Gly384Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant has been reported in several individuals affected with craniosynostosis (PMID: 24127277, 8946174). In one of these individuals, this variant was reported to be de novo (PMID: 8946174). -

Acrocephalosyndactyly type I;C0010273:Crouzon syndrome;C0038356:Neoplasm of stomach;C0175699:Saethre-Chotzen syndrome;C0220658:Pfeiffer syndrome;C0265269:Levy-Hollister syndrome;C0795998:Jackson-Weiss syndrome;C1852406:Beare-Stevenson cutis gyrata syndrome;C1865070:Familial scaphocephaly syndrome, McGillivray type;C2936791:Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis;C3281247:Bent bone dysplasia syndrome 1 Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	.;.;.;D;.;.;D;.;D;.;.;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.1	.;.;.;M;.;.;.;M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.4	D;D;.;D;.;D;D;D;.;D;D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.027	D;D;.;D;.;D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.040	D;T;T;T;T;T;D;T;T;D;D;D;D;.
Polyphen		0.99, 0.99, 0.90, 1.0	.;D;.;D;.;D;.;.;.;.;P;D;.;.
Vest4		0.91
MutPred		0.90		.;.;.;Loss of catalytic residue at V385 (P = 0.0648);.;.;.;Loss of catalytic residue at V385 (P = 0.0648);.;.;.;.;.;.;
MVP		0.94
MPC		1.9
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.85
gMVP		0.90

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: rs1554927408; hg19: chr10-123274768; COSMIC: COSV60649627; COSMIC: COSV60649627;