rs121918510

Positions:

• chr10-121517441-T-A
• chr10-121517441-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3 PP5_Moderate

The NM_000141.5(FGFR2):​c.962A>T​(p.Asp321Val) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.96

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 8 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771
• PP5: Variant 10-121517441-T-A is Pathogenic according to our data. Variant chr10-121517441-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 1060632.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.962A>T	p.Asp321Val	missense_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.962A>T	p.Asp321Val	missense_variant	8/18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000613048.4	c.695A>T	p.Asp232Val	missense_variant	7/17	5		ENSP00000484154.1
FGFR2	ENST00000478859.5	c.278A>T	p.Asp93Val	missense_variant	7/17	1		ENSP00000474011.1
FGFR2	ENST00000457416.7	c.1087+1241A>T		intron_variant		1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1087+1241A>T		intron_variant		1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1087+1241A>T		intron_variant		1		ENSP00000358054.3
FGFR2	ENST00000369061.8	c.749-2122A>T		intron_variant		1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.742+1241A>T		intron_variant		5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.820+1241A>T		intron_variant		2		ENSP00000353262.3
FGFR2	ENST00000604236.5	n.*9A>T		non_coding_transcript_exon_variant	7/17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*9A>T		3_prime_UTR_variant	7/17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

FGFR2-related craniosynostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 07, 2022

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FGFR2 protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp321 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7719333, 9531645, 9586546, 10394936). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1060632). This missense change has been observed in individuals with clinical features of FGFR2-related conditions (PMID: 29109840; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 321 of the FGFR2 protein (p.Asp321Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	.;.;D;.;.;.;T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.7	.;.;L;.;.;L;.;.
PROVEAN	Uncertain	-4.2	D;.;D;.;D;D;.;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.028	D;.;D;.;D;D;.;D
Sift4G	Benign	0.072	T;T;T;T;T;T;D;.
Polyphen		0.012	B;.;.;.;B;.;.;.
Vest4		0.94
MutPred		0.39		.;.;Gain of methylation at K322 (P = 0.045);.;.;Gain of methylation at K322 (P = 0.045);.;.;
MVP		0.91
ClinPred		0.87	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69

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: chr10-123276955;