10-121479598-G-C

Position:

• chr10-121479598-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001144915.2(FGFR2):​c.2107C>G​(p.Leu703Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L703L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR2 NM_001144915.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FGFR2. . Gene score misZ: 2.402 (greater than the threshold 3.09). Trascript score misZ: 4.3438 (greater than threshold 3.09). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. GenCC has associacion of the gene with Pfeiffer syndrome type 3, Antley-Bixler syndrome, Pfeiffer syndrome type 2, Saethre-Chotzen syndrome, Beare-Stevenson cutis gyrata syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Pfeiffer syndrome type 1, LADD syndrome 1, Pfeiffer syndrome, bent bone dysplasia syndrome 1, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis, familial scaphocephaly syndrome, McGillivray type, Apert syndrome, LADD syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16966859).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.*259C>G		3_prime_UTR_variant	18/18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487	c.*259C>G		3_prime_UTR_variant	18/18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416	c.*259C>G		3_prime_UTR_variant	18/18	1		ENSP00000410294.2
FGFR2	ENST00000613048	c.*259C>G		3_prime_UTR_variant	17/17	5		ENSP00000484154.1
FGFR2	ENST00000369061	c.*259C>G		3_prime_UTR_variant	15/15	1		ENSP00000358057.4
FGFR2	ENST00000478859	c.*259C>G		3_prime_UTR_variant	17/17	1		ENSP00000474011.1
FGFR2	ENST00000604236.5	n.*1772C>G		non_coding_transcript_exon_variant	17/17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*1772C>G		3_prime_UTR_variant	17/17	1		ENSP00000474109.1
FGFR2	ENST00000369059.5	c.*259C>G		downstream_gene_variant		5		ENSP00000358055.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	13
DANN	Benign	0.069
Eigen	Benign	-0.039
Eigen_PC	Benign	0.091
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.58	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.25
Sift	Benign	0.12	T
Sift4G	Benign	0.24	T
Polyphen		0.030	B
Vest4		0.14
MutPred		0.29		Gain of catalytic residue at L703 (P = 0.027);
MVP		0.54
ClinPred		0.13	T
GERP RS		4.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1047057; hg19: chr10-123239112;