dbSNP rs3135802: FGFR2:c.1867-17T>G (chr10-121488130-A-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000141.5(FGFR2):c.1864-17T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0224 in 1,612,798 control chromosomes in the GnomAD database, including 484 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 50 hom., cov: 33)

Exomes 𝑓: 0.023 ( 434 hom. )

Consequence

FGFR2
NM_000141.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.345

Publications

7 publications found

Variant links:

COSMIC-nc: COSV60640599

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=-0.83).

BP6

Variant 10-121488130-A-C is Benign according to our data. Variant chr10-121488130-A-C is described in ClinVar as Benign. ClinVar VariationId is 255315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0206 (3123/151502) while in subpopulation NFE AF = 0.0254 (1722/67908). AF 95% confidence interval is 0.0244. There are 50 homozygotes in GnomAd4. There are 1511 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 3123 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000141.5. 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.1867-17T>G	intron	N/A	NP_075259.4
FGFR2	NM_000141.5	MANE Select	c.1864-17T>G	intron	N/A	NP_000132.3
FGFR2	NM_001441087.1		c.1861-17T>G	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.1867-17T>G	intron	N/A	ENSP00000410294.2
FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.1864-17T>G	intron	N/A	ENSP00000351276.6
FGFR2	ENST00000369056.5	TSL:1	c.1867-17T>G	intron	N/A	ENSP00000358052.1

Frequencies

GnomAD3 genomes

AF:

0.0206

AC:

3124

AN:

151384

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0146

Gnomad AMI

AF:

0.0210

Gnomad AMR

AF:

0.0163

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.0106

Gnomad SAS

AF:

0.00602

Gnomad FIN

AF:

0.0322

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0254

Gnomad OTH

AF:

0.0212

GnomAD2 exomes

AF:

0.0191

AC:

4797

AN:

250920

AF XY:

0.0191

show subpopulations

Gnomad AFR exome

AF:

0.0148

Gnomad AMR exome

AF:

0.0122

Gnomad ASJ exome

AF:

0.0164

Gnomad EAS exome

AF:

0.0152

Gnomad FIN exome

AF:

0.0344

Gnomad NFE exome

AF:

0.0233

Gnomad OTH exome

AF:

0.0243

GnomAD4 exome

AF:

0.0226

AC:

32986

AN:

1461296

Hom.:

434

Cov.:

AF XY:

0.0219

AC XY:

15948

AN XY:

726984

show subpopulations

African (AFR)

AF:

0.0169

AC:

566

AN:

33470

American (AMR)

AF:

0.0125

AC:

558

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0166

AC:

435

AN:

26134

East Asian (EAS)

AF:

0.00781

AC:

310

AN:

39698

South Asian (SAS)

AF:

0.00601

AC:

518

AN:

86258

European-Finnish (FIN)

AF:

0.0349

AC:

1854

AN:

53130

Middle Eastern (MID)

AF:

0.0499

AC:

288

AN:

5766

European-Non Finnish (NFE)

AF:

0.0243

AC:

26988

AN:

1111738

Other (OTH)

AF:

0.0243

AC:

1469

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

1453

2906

4358

5811

7264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1012

2024

3036

4048

5060

<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:

0.0206

AC:

3123

AN:

151502

Hom.:

Cov.:

AF XY:

0.0204

AC XY:

1511

AN XY:

74048

show subpopulations

African (AFR)

AF:

0.0146

AC:

599

AN:

41074

American (AMR)

AF:

0.0163

AC:

249

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.0167

AC:

AN:

3464

East Asian (EAS)

AF:

0.0106

AC:

AN:

5192

South Asian (SAS)

AF:

0.00581

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0322

AC:

338

AN:

10488

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0254

AC:

1722

AN:

67908

Other (OTH)

AF:

0.0210

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

158

316

475

633

791

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0208

Hom.:

Bravo

AF:

0.0191

Asia WGS

AF:

0.0150

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (2)

FGFR2-related craniosynostosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.2

(source)

DANN

Benign

0.61

PhyloP100

-0.34

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over