10-121580917-GC-G

Variant names:

• chr10-121580917-GC-G
• rs35054928
• NM_000141.5:c.109+12791delG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000141.5(FGFR2):​c.109+12791delG variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.53 (21759 hom., cov: 0)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00
• Publications: 36 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 -10 ACMG points.

• BP6: Variant 10-121580917-GC-G is Benign according to our data. Variant chr10-121580917-GC-G is described in ClinVar as Benign. ClinVar VariationId is 1659816.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.109+12791delG		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+12791delG		intron_variant	Intron 2 of 17	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.109+12791delG		intron_variant	Intron 2 of 17	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.109+12791delG		intron_variant	Intron 1 of 16	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.109+12791delG		intron_variant	Intron 2 of 16	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.109+12791delG		intron_variant	Intron 2 of 16	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.109+12791delG		intron_variant	Intron 1 of 14	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.109+12791delG		intron_variant	Intron 2 of 15	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.109+12791delG		intron_variant	Intron 2 of 16	2		ENSP00000353262.3
FGFR2	ENST00000604236.5	n.109+12791delG		intron_variant	Intron 2 of 16	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80129 AN: 151834 Hom.: 21732 Cov.: 0

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.566

Gnomad ASJ AF: 0.574

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.603

Gnomad FIN AF: 0.566

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.548

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

GnomAD4 genome AF: 0.528 AC: 80192 AN: 151954 Hom.: 21759 Cov.: 0 AF XY: 0.526 AC XY: 39067 AN XY: 74254

African (AFR) AF: 0.383 AC: 15890 AN: 41470

American (AMR) AF: 0.566 AC: 8648 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 1989 AN: 3466

East Asian (EAS) AF: 0.551 AC: 2823 AN: 5128

South Asian (SAS) AF: 0.603 AC: 2901 AN: 4810

European-Finnish (FIN) AF: 0.566 AC: 5970 AN: 10556

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.593 AC: 40286 AN: 67940

Other (OTH) AF: 0.553 AC: 1166 AN: 2110

Alfa AF: 0.574 Hom.: 3092

Bravo AF: 0.520

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

FGFR2-related craniosynostosis Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
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: rs35054928; hg19: chr10-123340431;