rs1057519854

Positions:

• chr10-121488063-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000141.5(FGFR2):​c.1914T>A​(p.Asn638Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:5
• Conservation: PhyloP100: -0.0820

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 2 ACMG points.

• 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=0.41884705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1914T>A	p.Asn638Lys	missense_variant	14/18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1914T>A	p.Asn638Lys	missense_variant	14/18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.1917T>A	p.Asn639Lys	missense_variant	14/18	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1917T>A	p.Asn639Lys	missense_variant	13/17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1917T>A	p.Asn639Lys	missense_variant	14/17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.1647T>A	p.Asn549Lys	missense_variant	13/17	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.1578T>A	p.Asn526Lys	missense_variant	11/15	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.1572T>A	p.Asn524Lys	missense_variant	12/16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.1650T>A	p.Asn550Lys	missense_variant	13/17	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.1230T>A	p.Asn410Lys	missense_variant	13/17	1		ENSP00000474011.1
FGFR2	ENST00000429361.5	c.690T>A	p.Asn230Lys	missense_variant	6/9	5		ENSP00000404219.1
FGFR2	ENST00000604236.5	n.*961T>A		non_coding_transcript_exon_variant	13/17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*961T>A		3_prime_UTR_variant	13/17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: no assertion criteria provided

Submissions by phenotype

Endometrium neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Malignant neoplasm of body of uterus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Breast neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Nasopharyngeal neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Lung adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	.;.;.;D;.;.;.;D;D;.;T;.;.;.;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.42	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.077	D
MutationAssessor	Benign	-0.28	.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.9	D;D;.;D;.;D;D;D;D;D;.;D;D;D;D;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D;.;D;.;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.87, 0.99, 0.99, 0.16, 1.0	.;P;.;D;.;D;.;.;.;.;.;.;B;D;.;.
Vest4		0.67
MutPred		0.57		.;.;.;Gain of ubiquitination at N638 (P = 0.0452);.;.;.;.;.;.;Gain of ubiquitination at N638 (P = 0.0452);.;.;.;.;.;
MVP		0.85
MPC		1.3
ClinPred		0.87	D
GERP RS		-2.6
Varity_R		0.87
gMVP		0.89

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: rs1057519854; hg19: chr10-123247577;