rs1358919643

Positions:

• chr10-121517463-C-A
• chr10-121517463-C-G
• chr10-121517463-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PP2 PP5 BP4

The NM_000141.5(FGFR2):​c.940G>T​(p.Ala314Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR2 NM_000141.5 missense, splice_region
• Scores: Splicing: ADA: 0.8761
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.62

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a disulfide_bond (size 64) in uniprot entity FGFR2_HUMAN there are 35 pathogenic changes around while only 1 benign (97%) in NM_000141.5
• 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.
• PP5: Variant 10-121517463-C-A is Pathogenic according to our data. Variant chr10-121517463-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 478049.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34725863). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.940G>T	p.Ala314Ser	missense_variant, splice_region_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.940G>T	p.Ala314Ser	missense_variant, splice_region_variant	8/18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000613048.4	c.673G>T	p.Ala225Ser	missense_variant, splice_region_variant	7/17	5		ENSP00000484154.1
FGFR2	ENST00000478859.5	c.256G>T	p.Ala86Ser	missense_variant, splice_region_variant	7/17	1		ENSP00000474011.1
FGFR2	ENST00000457416.7	c.1087+1219G>T		intron_variant		1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1087+1219G>T		intron_variant		1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1087+1219G>T		intron_variant		1		ENSP00000358054.3
FGFR2	ENST00000369061.8	c.749-2144G>T		intron_variant		1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.742+1219G>T		intron_variant		5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.820+1219G>T		intron_variant		2		ENSP00000353262.3
FGFR2	ENST00000604236.5	n.743G>T		splice_region_variant, non_coding_transcript_exon_variant	7/17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

FGFR2-related craniosynostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2021

This sequence change replaces alanine with serine at codon 314 of the FGFR2 protein (p.Ala314Ser). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with clinical features of FGFR2-related disorder (Invitae). This variant has also been reported in an individual with craniosynostosis (PMID: 9521581) and it has been reported in 2 individuals with Pfeiffer syndrome (PMID: 7795583). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2020

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 15565658, 21367659, 29230096, 10951518, 9521581, 8298735, 7795583, 8528214) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	.;.;T;.;.;.;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;T;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.075	.;.;N;.;.;N;.;.
PROVEAN	Benign	0.49	N;.;N;.;N;N;.;N
REVEL	Benign	0.19
Sift	Benign	0.18	T;.;T;.;T;T;.;T
Sift4G	Benign	0.72	T;T;T;T;T;T;T;.
Polyphen		0.0	B;.;.;.;B;.;.;.
Vest4		0.59
MutPred		0.70		.;.;Gain of methylation at K310 (P = 0.0919);.;.;Gain of methylation at K310 (P = 0.0919);.;.;
MVP		0.89
ClinPred		0.76	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.88
dbscSNV1_RF	Pathogenic	0.74
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: rs1358919643; hg19: chr10-123276977;