10-121496705-C-T

Variant names:

• chr10-121496705-C-T
• rs1057519797
• NM_000141.5:c.1690G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000141.5(FGFR2):​c.1690G>A​(p.Val564Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.89

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the FGFR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 2.402 (below the threshold of 3.09). Trascript score misZ: 4.4365 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.779

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1690G>A	p.Val564Ile	missense_variant	Exon 13 of 18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1690G>A	p.Val564Ile	missense_variant	Exon 13 of 18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.1693G>A	p.Val565Ile	missense_variant	Exon 13 of 18	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1693G>A	p.Val565Ile	missense_variant	Exon 12 of 17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1693G>A	p.Val565Ile	missense_variant	Exon 13 of 17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.1423G>A	p.Val475Ile	missense_variant	Exon 12 of 17	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.1354G>A	p.Val452Ile	missense_variant	Exon 10 of 15	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.1348G>A	p.Val450Ile	missense_variant	Exon 11 of 16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.1426G>A	p.Val476Ile	missense_variant	Exon 12 of 17	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.1006G>A	p.Val336Ile	missense_variant	Exon 12 of 17	1		ENSP00000474011.1
FGFR2	ENST00000429361.5	c.466G>A	p.Val156Ile	missense_variant	Exon 5 of 9	5		ENSP00000404219.1
FGFR2	ENST00000604236.5	n.*737G>A		non_coding_transcript_exon_variant	Exon 12 of 17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*737G>A		3_prime_UTR_variant	Exon 12 of 17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 14, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously reported as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 26097890, 25349422, 25169980, 27109926, 28034880, 28427515, 28978721, 29540482) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	.;.;.;D;.;.;.;T;T;.;T;.;.;.;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	0.38	.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.86	N;N;.;N;.;N;N;N;N;N;.;N;N;N;N;N
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;T;.;T;.;T;D;T;D;T;.;T;T;T;T;T
Sift4G	Uncertain	0.038	D;T;T;D;T;T;T;T;T;D;D;D;T;D;D;.
Polyphen		0.63, 0.94, 0.38, 0.18, 0.99	.;P;.;P;.;B;.;.;.;.;.;.;B;D;.;.
Vest4		0.49
MutPred		0.67		.;.;.;Loss of catalytic residue at V564 (P = 0.089);.;.;.;.;.;.;Loss of catalytic residue at V564 (P = 0.089);.;.;.;.;.;
MVP		0.89
MPC		1.3
ClinPred		0.81	D
GERP RS		5.3
Varity_R		0.51
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519797; hg19: chr10-123256219;