rs2303568

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000141.5(FGFR2):c.454+54T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,521,000 control chromosomes in the GnomAD database, including 5,241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 2639 hom., cov: 32)

Exomes 𝑓: 0.018 ( 2602 hom. )

Consequence

FGFR2
NM_000141.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.229

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 10-121564448-A-G is Benign according to our data. Variant chr10-121564448-A-G is described in ClinVar as Benign. ClinVar VariationId is 1221381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5 link	c.454+54T>C		intron_variant	Intron 4 of 17	ENST00000358487.10	NP_000132.3	P21802-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
FGFR2	ENST00000358487.10 link	c.454+54T>C	intron_variant	Intron 4 of 17	1	NM_000141.5	ENSP00000351276.6	P21802-1
FGFR2	ENST00000457416.7 link	c.454+54T>C	intron_variant	Intron 4 of 17	1		ENSP00000410294.2	P21802-3
FGFR2	ENST00000369056.5 link	c.454+54T>C	intron_variant	Intron 3 of 16	1		ENSP00000358052.1	P21802-17
FGFR2	ENST00000369058.7 link	c.454+54T>C	intron_variant	Intron 4 of 16	1		ENSP00000358054.3	A0A5S6RJB7
FGFR2	ENST00000613048.4 link	c.187+54T>C	intron_variant	Intron 3 of 16	5		ENSP00000484154.1	D2CGD1
FGFR2	ENST00000369061.8 link	c.454+54T>C	intron_variant	Intron 3 of 14	1		ENSP00000358057.4	P21802-23
FGFR2	ENST00000369059.5 link	c.110-12989T>C	intron_variant	Intron 2 of 15	5		ENSP00000358055.1	E7EVR7
FGFR2	ENST00000360144.7 link	c.187+54T>C	intron_variant	Intron 3 of 16	2		ENSP00000353262.3	P21802-22
FGFR2	ENST00000604236.5 link	n.110-12989T>C	intron_variant	Intron 2 of 16	1		ENSP00000474109.1	S4R3B2

Frequencies

GnomAD3 genomes

AF:

0.110

AC:

16661

AN:

151838

Hom.:

2621

Cov.:

show subpopulations

Gnomad AFR

AF:

0.345

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0873

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.0734

Gnomad SAS

AF:

0.00752

Gnomad FIN

AF:

0.0302

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00262

Gnomad OTH

AF:

0.0822

GnomAD4 exome

AF:

0.0175

AC:

24014

AN:

1369042

Hom.:

2602

Cov.:

AF XY:

0.0154

AC XY:

10543

AN XY:

686418

show subpopulations

African (AFR)

AF:

0.358

AC:

11277

AN:

31534

American (AMR)

AF:

0.106

AC:

4728

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.000702

AC:

AN:

25638

East Asian (EAS)

AF:

0.0729

AC:

2863

AN:

39254

South Asian (SAS)

AF:

0.00344

AC:

291

AN:

84476

European-Finnish (FIN)

AF:

0.0288

AC:

1503

AN:

52186

Middle Eastern (MID)

AF:

0.0222

AC:

117

AN:

5276

European-Non Finnish (NFE)

AF:

0.00132

AC:

1357

AN:

1028712

Other (OTH)

AF:

0.0324

AC:

1860

AN:

57332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1101

2202

3304

4405

5506

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

424

848

1272

1696

2120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.110

AC:

16727

AN:

151958

Hom.:

2639

Cov.:

AF XY:

0.109

AC XY:

8132

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.346

AC:

14296

AN:

41358

American (AMR)

AF:

0.0880

AC:

1344

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.0726

AC:

374

AN:

5154

South Asian (SAS)

AF:

0.00753

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.0302

AC:

320

AN:

10606

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00262

AC:

178

AN:

67998

Other (OTH)

AF:

0.0818

AC:

173

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

561

1123

1684

2246

2807

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

296

444

592

740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0464

Hom.:

207

Bravo

AF:

0.126

Asia WGS

AF:

0.0570

AC:

199

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 25, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

9.7

(source)

DANN

Benign

0.63

PhyloP100

-0.23

Mutation Taster

=100/0

polymorphism (auto)

(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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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