10-121517465-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_022970.4(FGFR2):c.1087+1217A>C variant causes a intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

FGFR2
NM_022970.4 intron

Scores

Splicing: ADA: 0.9283

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.93

Publications

0 publications found

Variant links:

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

FGFR2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-121517465-T-G is Pathogenic according to our data. Variant chr10-121517465-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1685821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022970.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FGFR2	NM_022970.4	MANE Plus Clinical	c.1087+1217A>C	intron	N/A	NP_075259.4
FGFR2	NM_000141.5	MANE Select	c.940-2A>C	splice_acceptor intron	N/A	NP_000132.3
FGFR2	NM_001441087.1		c.1087+1217A>C	intron	N/A	NP_001428016.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FGFR2	ENST00000457416.7	TSL:1 MANE Plus Clinical	c.1087+1217A>C	intron	N/A	ENSP00000410294.2
FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.940-2A>C	splice_acceptor intron	N/A	ENSP00000351276.6
FGFR2	ENST00000369056.5	TSL:1	c.1087+1217A>C	intron	N/A	ENSP00000358052.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

FGFR2-related craniosynostosis

Pathogenic:1

Oct 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 1685821). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exons 7-8, but is expected to preserve the integrity of the reading-frame (PMID: 9973282). This variant is also known as c.1119-2A>C. Disruption of this splice site has been observed in individuals with Pfeiffer and Apert syndromes (PMID: 7795583, 16418739, 25271085, 270283566). 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 affects an acceptor splice site in intron 7 of the FGFR2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.

Acrocephalosyndactyly type I

Pathogenic:1

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.051

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

PhyloP100

7.9

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.93

dbscSNV1_RF

Pathogenic

0.81

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over