10-121498522-T-G

Variant names:

• chr10-121498522-T-G
• rs1057519045
• NM_000141.5:c.1645A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_000141.5(FGFR2):​c.1645A>C​(p.Asn549His) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 8.01

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 Likely_pathogenic. Variant got 9 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, 0.981
• PP5: Variant 10-121498522-T-G is Pathogenic according to our data. Variant chr10-121498522-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374821.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1645A>C	p.Asn549His	missense_variant	Exon 12 of 18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1645A>C	p.Asn549His	missense_variant	Exon 12 of 18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.1648A>C	p.Asn550His	missense_variant	Exon 12 of 18	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1648A>C	p.Asn550His	missense_variant	Exon 11 of 17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1648A>C	p.Asn550His	missense_variant	Exon 12 of 17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.1378A>C	p.Asn460His	missense_variant	Exon 11 of 17	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.1309A>C	p.Asn437His	missense_variant	Exon 9 of 15	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.1303A>C	p.Asn435His	missense_variant	Exon 10 of 16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.1381A>C	p.Asn461His	missense_variant	Exon 11 of 17	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.961A>C	p.Asn321His	missense_variant	Exon 11 of 17	1		ENSP00000474011.1
FGFR2	ENST00000429361.5	c.421A>C	p.Asn141His	missense_variant	Exon 4 of 9	5		ENSP00000404219.1
FGFR2	ENST00000604236.5	n.*692A>C		non_coding_transcript_exon_variant	Exon 11 of 17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*692A>C		3_prime_UTR_variant	Exon 11 of 17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Crouzon syndrome Pathogenic:1

Sep 17, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pemigatinib resistance Other:1

May 17, 2019

OSU Cancer Genomics Laboratory, Ohio State University Medical Center

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: in vitro;research

The Asn549His variant in FGFR2 was detected following 5 months of Pemigatinib therapy. In vitro functional studies also showed resistance to Pemigatinib. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	.;.;.;D;.;.;.;D;D;.;T;.;.;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	1.0	.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.2	D;D;.;D;.;D;D;D;D;D;.;D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D;.;D;.;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		1.0	.;D;.;D;.;D;.;.;.;.;.;.;D;D;.;.
Vest4		0.88
MutPred		0.94		.;.;.;Gain of catalytic residue at L551 (P = 0.073);.;.;.;.;.;.;Gain of catalytic residue at L551 (P = 0.073);.;.;.;.;.;
MVP		0.88
MPC		1.9
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.93
gMVP		0.77

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

LitVar

Other links and lift over

dbSNP: rs1057519045; hg19: chr10-123258036; COSMIC: COSV60640393;