rs3135812

Variant names:

• chr10-121483207-A-G
• rs3135812
• NM_000141.5:c.2301+491T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000141.5(FGFR2):​c.2301+491T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0248 in 152,364 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.025 (81 hom., cov: 33)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.203
• Publications: 2 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: Orphanet, ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• Beare-Stevenson cutis gyrata syndrome

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

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

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

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

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

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

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• familial scaphocephaly syndrome, McGillivray type

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

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0248 (3783/152364) while in subpopulation NFE AF = 0.0377 (2565/68044). AF 95% confidence interval is 0.0365. There are 81 homozygotes in GnomAd4. There are 1711 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3783 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.2301+491T>C		intron_variant	Intron 17 of 17	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.2301+491T>C		intron_variant	Intron 17 of 17	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.2304+491T>C		intron_variant	Intron 17 of 17	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.2304+491T>C		intron_variant	Intron 16 of 16	1		ENSP00000358052.1
FGFR2	ENST00000613048.4	c.2034+491T>C		intron_variant	Intron 16 of 16	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.1965+491T>C		intron_variant	Intron 14 of 14	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.1959+491T>C		intron_variant	Intron 15 of 15	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.2037+491T>C		intron_variant	Intron 16 of 16	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.1617+491T>C		intron_variant	Intron 16 of 16	1		ENSP00000474011.1
FGFR2	ENST00000429361.5	c.971+2188T>C		intron_variant	Intron 8 of 8	5		ENSP00000404219.1
FGFR2	ENST00000604236.5	n.*1348+491T>C		intron_variant	Intron 16 of 16	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3782 AN: 152246 Hom.: 81 Cov.: 33

Gnomad AFR AF: 0.00654

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0258

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0218

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0377

Gnomad OTH AF: 0.0330

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0248 AC: 3783 AN: 152364 Hom.: 81 Cov.: 33 AF XY: 0.0230 AC XY: 1711 AN XY: 74504

African (AFR) AF: 0.00652 AC: 271 AN: 41586

American (AMR) AF: 0.0257 AC: 394 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0421 AC: 146 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4822

European-Finnish (FIN) AF: 0.0218 AC: 232 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0377 AC: 2565 AN: 68044

Other (OTH) AF: 0.0326 AC: 69 AN: 2116

Alfa AF: 0.0330 Hom.: 142

Bravo AF: 0.0253

Asia WGS AF: 0.00375 AC: 15 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.75
DANN	Benign	0.66
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism

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: rs3135812; hg19: chr10-123242721; COSMIC: COSV60641202;