rs755793

Variant names:

• chr10-121551357-A-G
• rs755793
• NM_022970.4:c.557T>C

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M186V) has been classified as Likely 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:18 O:1
• Conservation: PhyloP100: 0.850
• Publications: 65 publications found

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 Gene-Disease associations (from GenCC):

• Apert syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, G2P, Orphanet
• Beare-Stevenson cutis gyrata syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, ClinGen, G2P
• bent bone dysplasia syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Crouzon syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Ambry Genetics, G2P
• Jackson-Weiss syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• LADD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Pfeiffer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
• Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
• familial scaphocephaly syndrome, McGillivray type

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Saethre-Chotzen syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Antley-Bixler syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LADD syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen
• Pfeiffer syndrome type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• 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, Crouzon syndrome, Apert syndrome, Antley-Bixler syndrome, Beare-Stevenson cutis gyrata syndrome, Jackson-Weiss syndrome, bent bone dysplasia syndrome 1, Pfeiffer syndrome, Saethre-Chotzen syndrome, LADD syndrome 1, familial scaphocephaly syndrome, McGillivray type, LADD syndrome, Pfeiffer syndrome type 1, Pfeiffer syndrome type 2, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis.
• 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 VariationId is 134392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000141.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	NM_022970.4	MANE Plus Clinical	c.557T>C	p.Met186Thr	missense	Exon 5 of 18	NP_075259.4	P21802-3
	FGFR2	NM_000141.5	MANE Select	c.557T>C	p.Met186Thr	missense	Exon 5 of 18	NP_000132.3	P21802-1
	FGFR2	NM_001441087.1		c.557T>C	p.Met186Thr	missense	Exon 5 of 18	NP_001428016.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	ENST00000457416.7	TSL:1 MANE Plus Clinical	c.557T>C	p.Met186Thr	missense	Exon 5 of 18	ENSP00000410294.2	P21802-3
	FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.557T>C	p.Met186Thr	missense	Exon 5 of 18	ENSP00000351276.6	P21802-1
	FGFR2	ENST00000369056.5	TSL:1	c.557T>C	p.Met186Thr	missense	Exon 4 of 17	ENSP00000358052.1	P21802-17

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

GnomAD2 exomes AF: 0.0454 AC: 11423 AN: 251474 AF XY: 0.0360

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 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

African (AFR) AF: 0.320 AC: 10710 AN: 33480

American (AMR) AF: 0.103 AC: 4585 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00287 AC: 75 AN: 26136

East Asian (EAS) AF: 0.0732 AC: 2906 AN: 39700

South Asian (SAS) AF: 0.00379 AC: 327 AN: 86258

European-Finnish (FIN) AF: 0.0289 AC: 1546 AN: 53420

Middle Eastern (MID) AF: 0.0225 AC: 130 AN: 5768

European-Non Finnish (NFE) AF: 0.00128 AC: 1419 AN: 1112012

Other (OTH) AF: 0.0300 AC: 1809 AN: 60396

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

African (AFR) AF: 0.308 AC: 12779 AN: 41508

American (AMR) AF: 0.0818 AC: 1252 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.0732 AC: 380 AN: 5190

South Asian (SAS) AF: 0.00787 AC: 38 AN: 4828

European-Finnish (FIN) AF: 0.0302 AC: 321 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00238 AC: 162 AN: 68036

Other (OTH) AF: 0.0733 AC: 155 AN: 2114

Alfa AF: 0.0346 Hom.: 1817

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	6	not specified (7)
-	-	1	Beare-Stevenson cutis gyrata syndrome (1)
-	-	1	Craniosynostosis syndrome (1)
-	-	1	Crouzon syndrome (1)
-	-	1	FGFR2-related craniosynostosis (1)
-	-	1	Isolated Coronal Synostosis (1)
-	-	1	Saethre-Chotzen syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.72	N
PhyloP100		0.85
PrimateAI	Benign	0.41	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.17
Sift	Benign	0.14	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.087
MPC		0.87
ClinPred		0.00016	T
GERP RS		3.9
Varity_R		0.092
gMVP		0.46
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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