10-121515280-T-A

Position:

• chr10-121515280-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP5_Moderate

The NM_000141.5(FGFR2):​c.1124A>T​(p.Tyr375Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y375C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.94

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-121515280-T-C is described in Lovd as [Likely_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.
• PP5: Variant 10-121515280-T-A is Pathogenic according to our data. Variant chr10-121515280-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3075688.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1124A>T	p.Tyr375Phe	missense_variant	9/18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1124A>T	p.Tyr375Phe	missense_variant	9/18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.1127A>T	p.Tyr376Phe	missense_variant	9/18	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1127A>T	p.Tyr376Phe	missense_variant	8/17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1127A>T	p.Tyr376Phe	missense_variant	9/17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.857A>T	p.Tyr286Phe	missense_variant	8/17	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.788A>T	p.Tyr263Phe	missense_variant	6/15	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.782A>T	p.Tyr261Phe	missense_variant	7/16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.860A>T	p.Tyr287Phe	missense_variant	8/17	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.440A>T	p.Tyr147Phe	missense_variant	8/17	1		ENSP00000474011.1
FGFR2	ENST00000604236.5	n.*171A>T		non_coding_transcript_exon_variant	8/17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*171A>T		3_prime_UTR_variant	8/17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pfeiffer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Medicine Lab, University of California San Francisco

Jul 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.63	.;.;.;D;.;.;T;.;T;.;.;.;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.062	D
MutationAssessor	Benign	1.8	.;.;.;L;.;.;.;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.2	N;D;.;D;.;D;D;D;.;D;D;D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.022	D;T;.;T;.;T;T;T;.;D;D;D;D;T
Sift4G	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.19, 0.094, 0.016, 0.0020, 0.19	.;B;.;B;.;B;.;.;.;.;B;B;.;.
Vest4		0.62
MutPred		0.59		.;.;.;Gain of sheet (P = 0.0827);.;.;.;Gain of sheet (P = 0.0827);.;.;.;.;.;.;
MVP		0.81
MPC		0.73
ClinPred		0.79	D
GERP RS		5.8
Varity_R		0.48
gMVP		0.78

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: chr10-123274794;