rs189179463

Variant names:

• chr10-121482172-T-A
• rs189179463
• ENST00000369056.5:c.2310A>T

Your query was ambiguous. Multiple possible variants found:

• chr10-121482172-T-A
• chr10-121482172-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The ENST00000369056.5(FGFR2):​c.2310A>T​(p.Ter770Cysext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR2 ENST00000369056.5 stop_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0400
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in ENST00000369056.5 Downstream stopcodon found after 777 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.2301+1526A>T		intron_variant	Intron 17 of 17	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000369056.5	c.2310A>T	p.Ter770Cysext*?	stop_lost	Exon 17 of 17	1		ENSP00000358052.1
FGFR2	ENST00000360144.7	c.2043A>T	p.Ter681Cysext*?	stop_lost	Exon 17 of 17	2		ENSP00000353262.3
FGFR2	ENST00000358487.10	c.2301+1526A>T		intron_variant	Intron 17 of 17	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.2304+1526A>T		intron_variant	Intron 17 of 17	1		ENSP00000410294.2
FGFR2	ENST00000613048.4	c.2034+1526A>T		intron_variant	Intron 16 of 16	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.1965+1526A>T		intron_variant	Intron 14 of 14	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.1959+1526A>T		intron_variant	Intron 15 of 15	5		ENSP00000358055.1
FGFR2	ENST00000478859.5	c.1617+1526A>T		intron_variant	Intron 16 of 16	1		ENSP00000474011.1
FGFR2	ENST00000429361.5	c.972-2151A>T		intron_variant	Intron 8 of 8	5		ENSP00000404219.1
FGFR2	ENST00000604236.5	n.*1348+1526A>T		intron_variant	Intron 16 of 16	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	14
DANN	Benign	0.81
Eigen	Benign	-0.057
Eigen_PC	Benign	-0.032
FATHMM_MKL	Benign	0.58	D
PhyloP100		0.040
Vest4		0.16
GERP RS		3.4
Mutation Taster		=55/145	disease causing

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: rs189179463; hg19: chr10-123241686;