rs755793

chr10-121551357-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000141.5(FGFR2):c.557T>C(p.Met186Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0239 in 1,614,158 control chromosomes in the GnomAD database, including 4,341 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (2074 hom., cov: 33)
  • Exomes 𝑓: 0.016 (2267 hom.)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: 0.850

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FGFR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0021749437).
• BP6: Variant 10-121551357-A-G is Benign according to our data. Variant chr10-121551357-A-G is described in ClinVar as [Benign]. Clinvar id is 134392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121551357-A-G is described in Lovd as [Benign]. Variant chr10-121551357-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR2	NM_022970.4	c.557T>C	p.Met186Thr	missense_variant	5/18	ENST00000457416.7
FGFR2	NM_000141.5	c.557T>C	p.Met186Thr	missense_variant	5/18	ENST00000358487.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR2	ENST00000457416.7	c.557T>C	p.Met186Thr	missense_variant	5/18	1	NM_022970.4	P4
FGFR2	ENST00000358487.10	c.557T>C	p.Met186Thr	missense_variant	5/18	1	NM_000141.5	A2

Frequencies

GnomAD3 genomes AF: 0.0991 AC: 15077 AN: 152148 Hom.: 2056 Cov.: 33

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0810

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.0740

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.0302

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00238

Gnomad OTH AF: 0.0736

GnomAD3 exomes AF: 0.0454 AC: 11423 AN: 251474 Hom.: 1083 AF XY: 0.0360 AC XY: 4891 AN XY: 135912

Gnomad AFR exome AF: 0.315

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.0790

Gnomad SAS exome AF: 0.00366

Gnomad FIN exome AF: 0.0295

Gnomad NFE exome AF: 0.00259

Gnomad OTH exome AF: 0.0290

GnomAD4 exome AF: 0.0161 AC: 23507 AN: 1461892 Hom.: 2267 Cov.: 32 AF XY: 0.0142 AC XY: 10326 AN XY: 727248

Gnomad4 AFR exome AF: 0.320

Gnomad4 AMR exome AF: 0.103

Gnomad4 ASJ exome AF: 0.00287

Gnomad4 EAS exome AF: 0.0732

Gnomad4 SAS exome AF: 0.00379

Gnomad4 FIN exome AF: 0.0289

Gnomad4 NFE exome AF: 0.00128

Gnomad4 OTH exome AF: 0.0300

GnomAD4 genome AF: 0.0994 AC: 15142 AN: 152266 Hom.: 2074 Cov.: 33 AF XY: 0.0987 AC XY: 7349 AN XY: 74464

Gnomad4 AFR AF: 0.308

Gnomad4 AMR AF: 0.0818

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.0732

Gnomad4 SAS AF: 0.00787

Gnomad4 FIN AF: 0.0302

Gnomad4 NFE AF: 0.00238

Gnomad4 OTH AF: 0.0733

Alfa AF: 0.0213 Hom.: 739

Bravo AF: 0.115

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.294 AC: 1295

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.0473 AC: 5745

Asia WGS AF: 0.0560 AC: 196 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00273

ClinVar

Significance: Benign

Submissions summary: Benign:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Mar 25, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 04, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

FGFR2-related craniosynostosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Crouzon syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Beare-Stevenson cutis gyrata syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Isolated coronal synostosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Craniosynostosis syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Saethre-Chotzen syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	14
Dann	Benign	0.31
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0022	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.72	N;.;.;N;.;N;.;N;.;N;.;N;N;.;N
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	1.3	N;N;.;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.14	T;T;.;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.81	T;T;T;T;T;T;T;T;T;T;T;T;T;.;T
Polyphen		0.0	.;B;.;B;B;.;.;.;.;.;B;B;.;.;.
Vest4		0.087
MPC		0.87
ClinPred		0.00016	T
GERP RS		3.9
Varity_R		0.092
gMVP		0.46

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: rs755793; hg19: chr10-123310871; COSMIC: COSV60642616;