10-121488035-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000141.5(FGFR2):c.1942G>A(p.Ala648Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar 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:5
• Conservation: PhyloP100: 7.87

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 17 ACMG points.

• PM1: In a domain Protein kinase (size 289) in uniprot entity FGFR2_HUMAN there are 49 pathogenic changes around while only 5 benign (91%) in NM_000141.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FGFR2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 10-121488035-C-T is Pathogenic according to our data. Variant chr10-121488035-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121488035-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR2	NM_022970.4	c.1945G>A	p.Ala649Thr	missense_variant	14/18	ENST00000457416.7
FGFR2	NM_000141.5	c.1942G>A	p.Ala648Thr	missense_variant	14/18	ENST00000358487.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR2	ENST00000457416.7	c.1945G>A	p.Ala649Thr	missense_variant	14/18	1	NM_022970.4	P4
FGFR2	ENST00000358487.10	c.1942G>A	p.Ala648Thr	missense_variant	14/18	1	NM_000141.5	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461850 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2023	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: 23754559, 16501574, 31502745) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -

Levy-Hollister syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jan 01, 2014	- -

FGFR2-related craniosynostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 22, 2023

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 13296). This missense change has been observed in individuals with lacrimoauriculodentodigital syndrome and/or radial anomalies (PMID: 16501574, 31502745). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 648 of the FGFR2 protein (p.Ala648Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.5	D;D;.;D;.;D;D;D;D;D;.;D;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;.;D;.;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.025	D;D;D;D;D;D;D;D;T;D;D;D;D;D;D;.
Polyphen		1.0	.;D;.;D;.;D;.;.;.;.;.;.;D;D;.;.
Vest4		0.86
MutPred		0.97		.;.;.;Loss of catalytic residue at A648 (P = 0.0371);.;.;.;.;.;.;Loss of catalytic residue at A648 (P = 0.0371);.;.;.;.;.;
MVP		0.96
MPC		1.6
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.88
gMVP		0.88

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: rs121918508; hg19: chr10-123247549; COSMIC: COSV60650006; COSMIC: COSV60650006;