10-121517379-A-T

Variant names:

• chr10-121517379-A-T
• rs121918488
• NM_000141.5:c.1024T>A

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000141.5(FGFR2):​c.1024T>A​(p.Cys342Ser) 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. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C342F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.26

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 Pathogenic. Variant got 23 ACMG points.

• PS1: Transcript NM_000141.5 (FGFR2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a strand (size 8) in uniprot entity FGFR2_HUMAN there are 20 pathogenic changes around while only 0 benign (100%) in NM_000141.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-121517378-C-A is described in Lovd as [Pathogenic].
• 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, 0.993
• PP5: Variant 10-121517379-A-T is Pathogenic according to our data. Variant chr10-121517379-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 13267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121517379-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1024T>A	p.Cys342Ser	missense_variant	Exon 8 of 18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1024T>A	p.Cys342Ser	missense_variant	Exon 8 of 18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000613048.4	c.757T>A	p.Cys253Ser	missense_variant	Exon 7 of 17	5		ENSP00000484154.1
FGFR2	ENST00000478859.5	c.340T>A	p.Cys114Ser	missense_variant	Exon 7 of 17	1		ENSP00000474011.1
FGFR2	ENST00000457416.7	c.1087+1303T>A		intron_variant	Intron 8 of 17	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1087+1303T>A		intron_variant	Intron 7 of 16	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1087+1303T>A		intron_variant	Intron 8 of 16	1		ENSP00000358054.3
FGFR2	ENST00000369061.8	c.749-2060T>A		intron_variant	Intron 5 of 14	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.742+1303T>A		intron_variant	Intron 6 of 15	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.820+1303T>A		intron_variant	Intron 7 of 16	2		ENSP00000353262.3
FGFR2	ENST00000604236.5	n.*71T>A		non_coding_transcript_exon_variant	Exon 7 of 17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*71T>A		3_prime_UTR_variant	Exon 7 of 17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Crouzon syndrome Pathogenic:2

Jan 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 04, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4 strong, PM2 moderate, PM5 moderate, PM6 moderate, PP3 supporting -

FGFR2-related craniosynostosis Pathogenic:1

Jan 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 342 of the FGFR2 protein (p.Cys342Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with syndromic craniosynostosis, including Pfeiffer and Crouzen syndromes (PMID: 7987400, 8644708, 9586546, 10541159, 12884424, 12884434, 24127277, 25271085, 26362256). ClinVar contains an entry for this variant (Variation ID: 13267). 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 with a positive predictive value of 95%. This variant disrupts the p.Cys342 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24127277). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Pfeiffer syndrome Pathogenic:1

Sep 17, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

May 31, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9385368, 10541159, 8644708, 25271085, 23754559, 7987400, 26362256, 10633130, 31122048, 30355600, 31618753) -

Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis Pathogenic:1

Jan 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jackson-Weiss syndrome Pathogenic:1

Jan 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	.;.;D;.;.;.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.4	.;.;H;.;.;H;.;.
PROVEAN	Pathogenic	-7.8	D;.;D;.;D;D;.;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;D;.;D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;.
Polyphen		1.0	D;.;.;.;D;.;.;.
Vest4		0.98
MutPred		0.97		.;.;Gain of disorder (P = 0.0049);.;.;Gain of disorder (P = 0.0049);.;.;
MVP		0.96
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs121918488; hg19: chr10-123276893;