rs56226109

Positions:

• chr10-121565644-G-A
• chr10-121565644-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000141.5(FGFR2):​c.170C>T​(p.Ser57Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00469 in 1,614,166 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (45 hom.)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: 4.72

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 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=0.010395318).
• BP6: Variant 10-121565644-G-A is Benign according to our data. Variant chr10-121565644-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121565644-G-A is described in Lovd as [Benign]. Variant chr10-121565644-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0032 (488/152282) while in subpopulation SAS AF= 0.0191 (92/4822). AF 95% confidence interval is 0.0159. There are 3 homozygotes in gnomad4. There are 252 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_022970.4	c.170C>T	p.Ser57Leu	missense_variant	3/18	ENST00000457416.7	NP_075259.4
FGFR2	NM_000141.5	c.170C>T	p.Ser57Leu	missense_variant	3/18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000457416.7	c.170C>T	p.Ser57Leu	missense_variant	3/18	1	NM_022970.4	ENSP00000410294	P4
FGFR2	ENST00000358487.10	c.170C>T	p.Ser57Leu	missense_variant	3/18	1	NM_000141.5	ENSP00000351276	A2

Frequencies

GnomAD3 genomes AF: 0.00321 AC: 488 AN: 152164 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00523

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00394

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00480 AC: 1206 AN: 251476 Hom.: 17 AF XY: 0.00597 AC XY: 812 AN XY: 135918

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0228

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00316

Gnomad OTH exome AF: 0.00472

GnomAD4 exome AF: 0.00485 AC: 7090 AN: 1461884 Hom.: 45 Cov.: 31 AF XY: 0.00551 AC XY: 4004 AN XY: 727244

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.00249

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0215

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.00425

Gnomad4 OTH exome AF: 0.00488

GnomAD4 genome AF: 0.00320 AC: 488 AN: 152282 Hom.: 3 Cov.: 32 AF XY: 0.00338 AC XY: 252 AN XY: 74462

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00523

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0191

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00394

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00366 Hom.: 3

Bravo AF: 0.00275

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00494 AC: 600

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00373

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2019	This variant is associated with the following publications: (PMID: 16912704, 24728327, 11781872, 23754559, 26429889) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 30, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2016	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

FGFR2-related craniosynostosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Crouzon syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Jan 13, 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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Craniosynostosis syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Jan 13, 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	0.067
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	.;T;.;.;T;.;.;.;.
Eigen	Benign	-0.077
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.010	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.24	N;N;N;N;.;N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.65	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.058
Sift	Uncertain	0.0020	D;T;T;T;T;T;T;T;T
Sift4G	Benign	0.45	T;T;T;T;T;T;T;T;T
Polyphen		0.0	.;B;.;.;.;.;B;.;.
Vest4		0.17
MVP		0.21
MPC		0.22
ClinPred		0.014	T
GERP RS		5.3
Varity_R		0.13
gMVP		0.32

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: rs56226109; hg19: chr10-123325158; COSMIC: COSV60663876;