rs121918506

Positions:

• chr10-121496701-T-A
• chr10-121496701-T-C
• chr10-121496701-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Strong

The NM_000141.5(FGFR2):​c.1694A>T​(p.Glu565Val) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E565A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.00

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-121496701-T-G is described in Lovd as [Pathogenic].
• 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 4.4365 (greater than threshold 3.09). GenCC has associacion of 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1694A>T	p.Glu565Val	missense_variant	13/18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1694A>T	p.Glu565Val	missense_variant	13/18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.1697A>T	p.Glu566Val	missense_variant	13/18	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1697A>T	p.Glu566Val	missense_variant	12/17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1697A>T	p.Glu566Val	missense_variant	13/17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.1427A>T	p.Glu476Val	missense_variant	12/17	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.1358A>T	p.Glu453Val	missense_variant	10/15	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.1352A>T	p.Glu451Val	missense_variant	11/16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.1430A>T	p.Glu477Val	missense_variant	12/17	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.1010A>T	p.Glu337Val	missense_variant	12/17	1		ENSP00000474011.1
FGFR2	ENST00000429361.5	c.470A>T	p.Glu157Val	missense_variant	5/9	5		ENSP00000404219.1
FGFR2	ENST00000604236.5	n.*741A>T		non_coding_transcript_exon_variant	12/17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*741A>T		3_prime_UTR_variant	12/17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	.;.;.;D;.;.;.;D;D;.;D;.;.;.;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	.;.;.;H;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.8	D;D;.;D;.;D;D;D;D;D;.;D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.;D;.;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.024	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		0.99, 1.0, 0.98, 1.0, 1.0	.;D;.;D;.;D;.;.;.;.;.;.;D;D;.;.
Vest4		0.99
MutPred		0.92		.;.;.;Loss of ubiquitination at K569 (P = 0.0468);.;.;.;.;.;.;Loss of ubiquitination at K569 (P = 0.0468);.;.;.;.;.;
MVP		0.97
MPC		1.9
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.94
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -15

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-123256215;