10-121520119-A-T

Position:

• chr10-121520119-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 7P and 2B. PM1 PM2 PM5 PP2 BP4_Moderate

The NM_000141.5(FGFR2):​c.799T>A​(p.Ser267Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S267P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.70

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain Ig-like C2-type 3 (size 102) in uniprot entity FGFR2_HUMAN there are 48 pathogenic changes around while only 2 benign (96%) in NM_000141.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-121520119-A-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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19158229).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.799T>A	p.Ser267Thr	missense_variant	7/18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.799T>A	p.Ser267Thr	missense_variant	7/18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.799T>A	p.Ser267Thr	missense_variant	7/18	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.799T>A	p.Ser267Thr	missense_variant	6/17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.799T>A	p.Ser267Thr	missense_variant	7/17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.532T>A	p.Ser178Thr	missense_variant	6/17	5		ENSP00000484154.1
FGFR2	ENST00000369059.5	c.454T>A	p.Ser152Thr	missense_variant	5/16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.532T>A	p.Ser178Thr	missense_variant	6/17	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.115T>A	p.Ser39Thr	missense_variant	6/17	1		ENSP00000474011.1
FGFR2	ENST00000369061.8	c.749-4800T>A		intron_variant		1		ENSP00000358057.4
FGFR2	ENST00000604236.5	n.454T>A		non_coding_transcript_exon_variant	5/17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 17, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 11781872, 29230096, 10394936, 7655462, 23348274) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Benign	0.31
DEOGEN2	Benign	0.30	.;.;T;.;.;.;T;.;T;.;.;.;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.099
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.83	T;T;T;T;D;T;T;T;T;T;T;T;T;D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	-1.2	.;.;N;.;.;N;.;N;.;N;.;N;N;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	1.6	N;.;N;.;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	1.0	T;.;T;.;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.0010	B;.;.;.;B;.;.;.;.;.;B;B;.;.
Vest4		0.15
MutPred		0.72		.;.;Gain of glycosylation at T268 (P = 0.2413);.;.;Gain of glycosylation at T268 (P = 0.2413);.;Gain of glycosylation at T268 (P = 0.2413);Gain of glycosylation at T268 (P = 0.2413);Gain of glycosylation at T268 (P = 0.2413);.;Gain of glycosylation at T268 (P = 0.2413);Gain of glycosylation at T268 (P = 0.2413);.;
MVP		0.54
MPC		1.1
ClinPred		0.57	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.49
gMVP		0.82

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-123279633;