rs45631563

Variant names:

• chr10-121589810-A-T
• rs45631563
• NM_000141.5:c.109+3899T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000141.5(FGFR2):​c.109+3899T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0365 in 152,352 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.037 (114 hom., cov: 33)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.43
• Publications: 29 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 10-121589810-A-T is Benign according to our data. Variant chr10-121589810-A-T is described in ClinVar as Benign. ClinVar VariationId is 1168306.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.109+3899T>A		intron_variant	Intron 2 of 17	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.109+3899T>A		intron_variant	Intron 2 of 17	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.109+3899T>A		intron_variant	Intron 2 of 17	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.109+3899T>A		intron_variant	Intron 1 of 16	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.109+3899T>A		intron_variant	Intron 2 of 16	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.109+3899T>A		intron_variant	Intron 2 of 16	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.109+3899T>A		intron_variant	Intron 1 of 14	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.109+3899T>A		intron_variant	Intron 2 of 15	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.109+3899T>A		intron_variant	Intron 2 of 16	2		ENSP00000353262.3
FGFR2	ENST00000604236.5	n.109+3899T>A		intron_variant	Intron 2 of 16	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes AF: 0.0366 AC: 5567 AN: 152234 Hom.: 114 Cov.: 33

Gnomad AFR AF: 0.00945

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0396

Gnomad ASJ AF: 0.0692

Gnomad EAS AF: 0.000768

Gnomad SAS AF: 0.0762

Gnomad FIN AF: 0.0512

Gnomad MID AF: 0.0860

Gnomad NFE AF: 0.0479

Gnomad OTH AF: 0.0544

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

GnomAD4 genome AF: 0.0365 AC: 5562 AN: 152352 Hom.: 114 Cov.: 33 AF XY: 0.0364 AC XY: 2710 AN XY: 74504

African (AFR) AF: 0.00945 AC: 393 AN: 41598

American (AMR) AF: 0.0395 AC: 604 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0692 AC: 240 AN: 3470

East Asian (EAS) AF: 0.000770 AC: 4 AN: 5194

South Asian (SAS) AF: 0.0760 AC: 367 AN: 4828

European-Finnish (FIN) AF: 0.0512 AC: 544 AN: 10618

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.0479 AC: 3259 AN: 68024

Other (OTH) AF: 0.0534 AC: 113 AN: 2116

Alfa AF: 0.0439 Hom.: 21

Bravo AF: 0.0333

Asia WGS AF: 0.0300 AC: 103 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

FGFR2-related craniosynostosis Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.47
CADD	Benign	16
DANN	Benign	0.80
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs45631563; hg19: chr10-123349324;