rs1219648

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is The variant received -14 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_Moderate

The NM_000141.5(FGFR2):c.109+7033T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.408 (AC=62,074) in the gnomAD database across 152,050 control chromosomes, including 12,688 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.421. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★).

Frequency

Genomes: 𝑓 0.41 ( 12688 hom., cov: 33)

Consequence

FGFR2
NM_000141.5 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.442

Publications

200 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: G2P, PanelApp Australia, ClinGen, Genomics England PanelApp, Orphanet
Beare-Stevenson cutis gyrata syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, ClinGen, Genomics England PanelApp
bent bone dysplasia syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Crouzon syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Ambry Genetics, ClinGen, Genomics England PanelApp, G2P
Jackson-Weiss syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
LADD syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
Pfeiffer syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, G2P, Ambry Genetics
Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
familial scaphocephaly syndrome, McGillivray type
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
Saethre-Chotzen syndrome
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
Antley-Bixler syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
LADD syndrome
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen
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
acinar dysplasia caused by mutation in FGFR2
Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

FGFR2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000141.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -14 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BP6

ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.4210 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000141.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FGFR2	NM_022970.4	MANE Plus Clinical	c.109+7033T>C	intron	N/A	NP_075259.4	P21802-3
FGFR2	NM_000141.5	MANE Select	c.109+7033T>C	intron	N/A	NP_000132.3	P21802-1
FGFR2	NM_001441087.1		c.109+7033T>C	intron	N/A	NP_001428016.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FGFR2	ENST00000457416.7	TSL:1 MANE Plus Clinical	c.109+7033T>C	intron	N/A	ENSP00000410294.2	P21802-3
FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.109+7033T>C	intron	N/A	ENSP00000351276.6	P21802-1
FGFR2	ENST00000369056.5	TSL:1	c.109+7033T>C	intron	N/A	ENSP00000358052.1	P21802-17

Frequencies

GnomAD3 genomes

AF:

0.408

AC:

62043

AN:

151932

Hom.:

12679

Cov.:

show subpopulations

Gnomad AFR

AF:

0.427

Gnomad AMI

AF:

0.548

Gnomad AMR

AF:

0.411

Gnomad ASJ

AF:

0.416

Gnomad EAS

AF:

0.379

Gnomad SAS

AF:

0.386

Gnomad FIN

AF:

0.431

Gnomad MID

AF:

0.446

Gnomad NFE

AF:

0.395

Gnomad OTH

AF:

0.408

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.408

AC:

62074

AN:

152050

Hom.:

12688

Cov.:

AF XY:

0.411

AC XY:

30552

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.426

AC:

17675

AN:

41464

American (AMR)

AF:

0.411

AC:

6282

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.416

AC:

1445

AN:

3472

East Asian (EAS)

AF:

0.378

AC:

1955

AN:

5172

South Asian (SAS)

AF:

0.387

AC:

1866

AN:

4816

European-Finnish (FIN)

AF:

0.431

AC:

4546

AN:

10554

Middle Eastern (MID)

AF:

0.432

AC:

127

AN:

294

European-Non Finnish (NFE)

AF:

0.395

AC:

26829

AN:

67978

Other (OTH)

AF:

0.403

AC:

851

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1925

3849

5774

7698

9623

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

594

1188

1782

2376

2970

<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:

0.399

Hom.:

54259

Bravo

AF:

0.408

Asia WGS

AF:

0.372

AC:

1294

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.363

AC:

44560

AN:

122678

Turkish Variome

AF:

0.435

AC:

672

AN:

1546

Hom.:

135

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.403

AC:

3607

AN:

8960

Hom.:

741

ABraOM SABE-WGS-1171

AF:

0.416

AC:

974

AN:

2342

Hom.:

208

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

FGFR2-related craniosynostosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.19

(source)

DANN

Benign

0.74

PhyloP100

-0.44

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over