NM_000141.5:c.1287+3485C>T

Variant names:

• chr10-121511632-G-A
• rs3750815
• NM_000141.5:c.1287+3485C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000141.5(FGFR2):​c.1287+3485C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0951 in 152,198 control chromosomes in the GnomAD database, including 781 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 0.095 (781 hom., cov: 33)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00400
• Publications: 6 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).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1287+3485C>T		intron_variant	Intron 9 of 17	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1287+3485C>T		intron_variant	Intron 9 of 17	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.1290+3485C>T		intron_variant	Intron 9 of 17	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1290+3485C>T		intron_variant	Intron 8 of 16	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1290+3485C>T		intron_variant	Intron 9 of 16	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.1020+3485C>T		intron_variant	Intron 8 of 16	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.951+3485C>T		intron_variant	Intron 6 of 14	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.945+3485C>T		intron_variant	Intron 7 of 15	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.1023+3485C>T		intron_variant	Intron 8 of 16	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.603+3485C>T		intron_variant	Intron 8 of 16	1		ENSP00000474011.1
FGFR2	ENST00000429361.5	c.63+3485C>T		intron_variant	Intron 1 of 8	5		ENSP00000404219.1
FGFR2	ENST00000604236.5	n.*334+3485C>T		intron_variant	Intron 8 of 16	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes AF: 0.0952 AC: 14472 AN: 152080 Hom.: 778 Cov.: 33

Gnomad AFR AF: 0.0512

Gnomad AMI AF: 0.0868

Gnomad AMR AF: 0.0869

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.0984

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.0932

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

GnomAD4 genome AF: 0.0951 AC: 14479 AN: 152198 Hom.: 781 Cov.: 33 AF XY: 0.0982 AC XY: 7307 AN XY: 74408

African (AFR) AF: 0.0511 AC: 2124 AN: 41552

American (AMR) AF: 0.0870 AC: 1331 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 391 AN: 3470

East Asian (EAS) AF: 0.0986 AC: 508 AN: 5152

South Asian (SAS) AF: 0.196 AC: 946 AN: 4818

European-Finnish (FIN) AF: 0.139 AC: 1467 AN: 10586

Middle Eastern (MID) AF: 0.121 AC: 35 AN: 290

European-Non Finnish (NFE) AF: 0.109 AC: 7401 AN: 68008

Other (OTH) AF: 0.0932 AC: 197 AN: 2114

Alfa AF: 0.104 Hom.: 552

Bravo AF: 0.0849

Asia WGS AF: 0.148 AC: 514 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	1.8
DANN	Benign	0.58
PhyloP100		0.0040
Mutation Taster		=100/0	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: rs3750815; hg19: chr10-123271146;