10-121517460-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 5P and 6B. PM1PM5PP2BP4BP6BS2

The NM_000141.5(FGFR2):c.943G>A(p.Ala315Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A315S) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

FGFR2
NM_000141.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 7.85

Publications

35 publications found

Variant links:

COSMIC-nc: COSV60645182

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000141.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-121517460-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 13289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.41775393).

BP6

Variant 10-121517460-C-T is Benign according to our data. Variant chr10-121517460-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3064171.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS2

High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5 link	c.943G>A	p.Ala315Thr	missense_variant	Exon 8 of 18	ENST00000358487.10	NP_000132.3	P21802-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FGFR2	ENST00000358487.10 link	c.943G>A	p.Ala315Thr	missense_variant	Exon 8 of 18	1	NM_000141.5	ENSP00000351276.6	P21802-1
FGFR2	ENST00000613048.4 link	c.676G>A	p.Ala226Thr	missense_variant	Exon 7 of 17	5		ENSP00000484154.1	D2CGD1
FGFR2	ENST00000478859.5 link	c.259G>A	p.Ala87Thr	missense_variant	Exon 7 of 17	1		ENSP00000474011.1	S4R381
FGFR2	ENST00000604236.5 link	n.746G>A		non_coding_transcript_exon_variant	Exon 7 of 17	1		ENSP00000474109.1	S4R3B2
FGFR2	ENST00000457416.7 link	c.1087+1222G>A		intron_variant	Intron 8 of 17	1		ENSP00000410294.2	P21802-3
FGFR2	ENST00000369056.5 link	c.1087+1222G>A		intron_variant	Intron 7 of 16	1		ENSP00000358052.1	P21802-17
FGFR2	ENST00000369058.7 link	c.1087+1222G>A		intron_variant	Intron 8 of 16	1		ENSP00000358054.3	A0A5S6RJB7
FGFR2	ENST00000369061.8 link	c.749-2141G>A		intron_variant	Intron 5 of 14	1		ENSP00000358057.4	P21802-23
FGFR2	ENST00000369059.5 link	c.742+1222G>A		intron_variant	Intron 6 of 15	5		ENSP00000358055.1	E7EVR7
FGFR2	ENST00000360144.7 link	c.820+1222G>A		intron_variant	Intron 7 of 16	2		ENSP00000353262.3	P21802-22

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251394

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111996

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41420

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 21, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign in association with an FGFR2-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 34426522, 11781872, 29230096, 28600779) -

Acrocephalosyndactyly type I;C0010273:Crouzon syndrome;C0024623:Gastric cancer;C0175699:Saethre-Chotzen syndrome;C0220658:Pfeiffer 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;C5774323:LADD syndrome 1

Benign:1

Jun 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pfeiffer syndrome

Benign:1

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

.;.;D;.;.;.;T;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D;D;D;D;D;T;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.42

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.23

.;.;N;.;.;N;.;.

PhyloP100

7.9

PROVEAN

Benign

-2.1

N;.;N;.;N;N;.;N

REVEL

Uncertain

0.34

Sift

Benign

0.12

T;.;T;.;T;T;.;T

Sift4G

Benign

0.17

T;T;T;T;T;T;T;.

Polyphen

0.045

B;.;.;.;B;.;.;.

Vest4

0.75

MVP

0.73

ClinPred

0.16

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

Mutation Taster

=0/100

disease causing

(source)

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

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10-121517460-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over