rs879253721

Variant names:

• chr10-121517316-T-C
• rs879253721
• NM_022970.4:c.1087+1366A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-121517316-T-C
• chr10-121517316-T-A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PM2 PP5_Very_Strong BP4

The NM_000141.5(FGFR2):​c.1084+3A>G variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001427227: "functional studies of this variant show aberrant splicing with two abnormal splice products present in patient cells (Kan et al., 2004)."" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR2 NM_000141.5 splice_region, intron
• Scores: Splicing: ADA: 0.2476
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.96
• Publications: 2 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, Genomics England PanelApp, G2P, ClinGen
• Beare-Stevenson cutis gyrata syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P, Genomics England PanelApp
• bent bone dysplasia syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• Crouzon syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Genomics England PanelApp, Ambry Genetics, Orphanet
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Pfeiffer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• 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: Orphanet, Genomics England PanelApp
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001427227: "functional studies of this variant show aberrant splicing with two abnormal splice products present in patient cells (Kan et al., 2004)."; SCV001581382: Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 15286168).; SCV002559332: Published functional studies demonstrate this variant leads to activation of an upstream cryptic donor splice site resulting in an in-frame variant (Kan et al., 2004)
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-121517316-T-C is Pathogenic according to our data. Variant chr10-121517316-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.18). . Strength limited to SUPPORTING due to the PP5.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	NM_022970.4	MANE Plus Clinical	c.1087+1366A>G		intron	N/A	NP_075259.4	P21802-3
	FGFR2	NM_000141.5	MANE Select	c.1084+3A>G		splice_region intron	N/A	NP_000132.3	P21802-1
	FGFR2	NM_001441087.1		c.1087+1366A>G		intron	N/A	NP_001428016.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	ENST00000457416.7	TSL:1 MANE Plus Clinical	c.1087+1366A>G		intron	N/A	ENSP00000410294.2	P21802-3
	FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.1084+3A>G		splice_region intron	N/A	ENSP00000351276.6	P21802-1
	FGFR2	ENST00000369056.5	TSL:1	c.1087+1366A>G		intron	N/A	ENSP00000358052.1	P21802-17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Pfeiffer syndrome (2)
1	-	-	Acrocephalosyndactyly type I;C0010273:Crouzon syndrome;C0220658:Pfeiffer syndrome (1)
1	-	-	Crouzon syndrome (1)
1	-	-	FGFR2-related craniosynostosis (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Benign	0.97
PhyloP100		8.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.25
dbscSNV1_RF	Benign	0.48
SpliceAI score (max)		0.020		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.

Other links and lift over

dbSNP: rs879253721;

hg19: chr10-123276830;