rs1358919643

Variant names:

• chr10-121517463-C-A
• rs1358919643
• NM_000141.5:c.940G>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 13/22 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). Synonymous variant affecting the same amino acid position (i.e. A314A) has been classified as Likely benign.

• 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
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• Apert syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• Beare-Stevenson cutis gyrata syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Genomics England PanelApp
• Crouzon syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, PanelApp Australia, Genomics England PanelApp, G2P
• Jackson-Weiss syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• LADD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Pfeiffer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
• bent bone dysplasia syndrome 1

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• familial scaphocephaly syndrome, McGillivray type

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• Saethre-Chotzen syndrome

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
• Antley-Bixler syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LADD syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000141.5
• 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, Crouzon syndrome, Apert syndrome, Antley-Bixler syndrome, Beare-Stevenson cutis gyrata syndrome, Jackson-Weiss syndrome, bent bone dysplasia syndrome 1, Pfeiffer syndrome, Saethre-Chotzen syndrome, LADD syndrome 1, familial scaphocephaly syndrome, McGillivray type, LADD syndrome, Pfeiffer syndrome type 1, Pfeiffer syndrome type 2, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis.
• 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 VariationId is 478049.
• 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 rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.940G>T	p.Ala314Ser	missense_variant, splice_region_variant	Exon 8 of 18	ENST00000358487.10	NP_000132.3
FGFR2	NM_022970.4	c.1087+1219G>T		intron_variant	Intron 8 of 17	ENST00000457416.7	NP_075259.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.940G>T	p.Ala314Ser	missense_variant, splice_region_variant	Exon 8 of 18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000613048.4	c.673G>T	p.Ala225Ser	missense_variant, splice_region_variant	Exon 7 of 17	5		ENSP00000484154.1
FGFR2	ENST00000478859.5	c.256G>T	p.Ala86Ser	missense_variant, splice_region_variant	Exon 7 of 17	1		ENSP00000474011.1
FGFR2	ENST00000604236.5	n.743G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 17	1		ENSP00000474109.1
FGFR2	ENST00000457416.7	c.1087+1219G>T		intron_variant	Intron 8 of 17	1	NM_022970.4	ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1087+1219G>T		intron_variant	Intron 7 of 16	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1087+1219G>T		intron_variant	Intron 8 of 16	1		ENSP00000358054.3
FGFR2	ENST00000369061.8	c.749-2144G>T		intron_variant	Intron 5 of 14	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.742+1219G>T		intron_variant	Intron 6 of 15	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.820+1219G>T		intron_variant	Intron 7 of 16	2		ENSP00000353262.3

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

Aug 24, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). 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 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). For these reasons, this variant has been classified as Pathogenic. 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. 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.

not provided Uncertain:1

Feb 24, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.0	.;.;T;.;.;.;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	0.10
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	0.0	.;.;N;.;.;N;.;.
PhyloP100		4.6
PROVEAN	Benign	0.49	N;.;N;.;N;N;.;N
Sift	Benign	0.18	T;.;T;.;T;T;.;T
Sift4G	Benign	0.72	T;T;T;T;T;T;T;.
Vest4		0.59
ClinPred		0.76	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1358919643; hg19: chr10-123276977;