rs1047057

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The ENST00000604236.5(FGFR2):n.*1772C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 1,550,826 control chromosomes in the GnomAD database, including 235,727 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 17607 hom., cov: 33)

Exomes 𝑓: 0.55 ( 218120 hom. )

Consequence

FGFR2
ENST00000604236.5 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 3.19

Publications

41 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=-0.65).

BP6

Variant 10-121479598-G-A is Benign according to our data. Variant chr10-121479598-G-A is described in ClinVar as [Benign]. Clinvar id is 298991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5 link	c.*259C>T		3_prime_UTR_variant	Exon 18 of 18	ENST00000358487.10	NP_000132.3	P21802-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
FGFR2	ENST00000604236.5 link	n.*1772C>T	non_coding_transcript_exon_variant	Exon 17 of 17	1		ENSP00000474109.1	S4R3B2
FGFR2	ENST00000358487.10 link	c.*259C>T	3_prime_UTR_variant	Exon 18 of 18	1	NM_000141.5	ENSP00000351276.6	P21802-1
FGFR2	ENST00000457416.7 link	c.*259C>T	3_prime_UTR_variant	Exon 18 of 18	1		ENSP00000410294.2	P21802-3
FGFR2	ENST00000613048.4 link	c.*259C>T	3_prime_UTR_variant	Exon 17 of 17	5		ENSP00000484154.1	D2CGD1
FGFR2	ENST00000369061.8 link	c.*259C>T	3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000358057.4	P21802-23
FGFR2	ENST00000478859.5 link	c.*259C>T	3_prime_UTR_variant	Exon 17 of 17	1		ENSP00000474011.1	S4R381
FGFR2	ENST00000604236.5 link	n.*1772C>T	3_prime_UTR_variant	Exon 17 of 17	1		ENSP00000474109.1	S4R3B2
FGFR2	ENST00000369059.5 link	c.*259C>T	downstream_gene_variant		5		ENSP00000358055.1	E7EVR7

Frequencies

GnomAD3 genomes

AF:

0.444

AC:

67496

AN:

151966

Hom.:

17592

Cov.:

show subpopulations

Gnomad AFR

AF:

0.157

Gnomad AMI

AF:

0.492

Gnomad AMR

AF:

0.633

Gnomad ASJ

AF:

0.589

Gnomad EAS

AF:

0.371

Gnomad SAS

AF:

0.599

Gnomad FIN

AF:

0.493

Gnomad MID

AF:

0.494

Gnomad NFE

AF:

0.554

Gnomad OTH

AF:

0.479

GnomAD2 exomes

AF:

0.555

AC:

85941

AN:

154958

AF XY:

0.555

show subpopulations

Gnomad AFR exome

AF:

0.147

Gnomad AMR exome

AF:

0.750

Gnomad ASJ exome

AF:

0.563

Gnomad EAS exome

AF:

0.380

Gnomad FIN exome

AF:

0.501

Gnomad NFE exome

AF:

0.557

Gnomad OTH exome

AF:

0.559

GnomAD4 exome

AF:

0.552

AC:

772464

AN:

1398742

Hom.:

218120

Cov.:

AF XY:

0.554

AC XY:

381978

AN XY:

689824

show subpopulations

African (AFR)

AF:

0.143

AC:

4528

AN:

31568

American (AMR)

AF:

0.732

AC:

26118

AN:

35664

Ashkenazi Jewish (ASJ)

AF:

0.561

AC:

14122

AN:

25172

East Asian (EAS)

AF:

0.391

AC:

13964

AN:

35720

South Asian (SAS)

AF:

0.596

AC:

47204

AN:

79180

European-Finnish (FIN)

AF:

0.501

AC:

24692

AN:

49272

Middle Eastern (MID)

AF:

0.480

AC:

2735

AN:

5696

European-Non Finnish (NFE)

AF:

0.564

AC:

608675

AN:

1078512

Other (OTH)

AF:

0.525

AC:

30426

AN:

57958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

16855

33710

50564

67419

84274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.444

AC:

67522

AN:

152084

Hom.:

17607

Cov.:

AF XY:

0.448

AC XY:

33284

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.157

AC:

6506

AN:

41500

American (AMR)

AF:

0.633

AC:

9671

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.589

AC:

2039

AN:

3464

East Asian (EAS)

AF:

0.373

AC:

1931

AN:

5180

South Asian (SAS)

AF:

0.600

AC:

2888

AN:

4812

European-Finnish (FIN)

AF:

0.493

AC:

5204

AN:

10566

Middle Eastern (MID)

AF:

0.497

AC:

146

AN:

294

European-Non Finnish (NFE)

AF:

0.554

AC:

37681

AN:

67980

Other (OTH)

AF:

0.477

AC:

1008

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1695

3389

5084

6778

8473

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.525

Hom.:

42631

Bravo

AF:

0.442

Asia WGS

AF:

0.476

AC:

1652

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 09, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Crouzon syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Beare-Stevenson cutis gyrata syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Isolated Coronal Synostosis

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Craniosynostosis syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Saethre-Chotzen syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.65

PhyloP100

3.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs1047057

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