10-121517463-C-T

Position:

• chr10-121517463-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_000141.5(FGFR2):​c.940G>A​(p.Ala314Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FGFR2 NM_000141.5 missense, splice_region
• Scores: Splicing: ADA: 0.004581
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.62

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 3 ACMG points.

• PM1: In a disulfide_bond (size 64) in uniprot entity FGFR2_HUMAN there are 35 pathogenic changes around while only 1 benign (97%) in NM_000141.5
• 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 4.4365 (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=0.106651604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.940G>A	p.Ala314Thr	missense_variant, splice_region_variant	8/18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.940G>A	p.Ala314Thr	missense_variant, splice_region_variant	8/18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000613048.4	c.673G>A	p.Ala225Thr	missense_variant, splice_region_variant	7/17	5		ENSP00000484154.1
FGFR2	ENST00000478859.5	c.256G>A	p.Ala86Thr	missense_variant, splice_region_variant	7/17	1		ENSP00000474011.1
FGFR2	ENST00000457416.7	c.1087+1219G>A		intron_variant		1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1087+1219G>A		intron_variant		1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1087+1219G>A		intron_variant		1		ENSP00000358054.3
FGFR2	ENST00000369061.8	c.749-2144G>A		intron_variant		1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.742+1219G>A		intron_variant		5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.820+1219G>A		intron_variant		2		ENSP00000353262.3
FGFR2	ENST00000604236.5	n.743G>A		splice_region_variant, non_coding_transcript_exon_variant	7/17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251396 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Benign	0.45
DEOGEN2	Benign	0.31	.;.;T;.;.;.;T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.020
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;T;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.63	.;.;N;.;.;N;.;.
PROVEAN	Benign	1.5	N;.;N;.;N;N;.;N
REVEL	Benign	0.073
Sift	Benign	1.0	T;.;T;.;T;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;.
Polyphen		0.0	B;.;.;.;B;.;.;.
Vest4		0.31
MutPred		0.46		.;.;Gain of methylation at K310 (P = 0.062);.;.;Gain of methylation at K310 (P = 0.062);.;.;
MVP		0.35
ClinPred		0.32	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0046
dbscSNV1_RF	Benign	0.084
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

LitVar

Other links and lift over

dbSNP: rs1358919643; hg19: chr10-123276977;