NM_000141.5:c.110-4211A>C

Variant names:

• chr10-121569915-T-G
• rs2981428
• NM_000141.5:c.110-4211A>C

Variant summary

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

The NM_000141.5(FGFR2):​c.110-4211A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 152,066 control chromosomes in the GnomAD database, including 17,014 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 0.43 (17014 hom., cov: 33)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.813
• Publications: 12 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.110-4211A>C		intron_variant	Intron 2 of 17	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.110-4211A>C		intron_variant	Intron 2 of 17	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.110-4211A>C		intron_variant	Intron 2 of 17	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.110-4211A>C		intron_variant	Intron 1 of 16	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.110-4211A>C		intron_variant	Intron 2 of 16	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.110-5336A>C		intron_variant	Intron 2 of 16	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.110-4211A>C		intron_variant	Intron 1 of 14	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.110-18456A>C		intron_variant	Intron 2 of 15	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.110-5336A>C		intron_variant	Intron 2 of 16	2		ENSP00000353262.3
FGFR2	ENST00000604236.5	n.110-18456A>C		intron_variant	Intron 2 of 16	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes AF: 0.428 AC: 65030 AN: 151948 Hom.: 17012 Cov.: 33

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.430

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.439

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

GnomAD4 genome AF: 0.428 AC: 65032 AN: 152066 Hom.: 17014 Cov.: 33 AF XY: 0.431 AC XY: 32027 AN XY: 74314

African (AFR) AF: 0.117 AC: 4852 AN: 41502

American (AMR) AF: 0.430 AC: 6568 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 1990 AN: 3470

East Asian (EAS) AF: 0.549 AC: 2823 AN: 5144

South Asian (SAS) AF: 0.540 AC: 2603 AN: 4822

European-Finnish (FIN) AF: 0.573 AC: 6061 AN: 10570

Middle Eastern (MID) AF: 0.469 AC: 137 AN: 292

European-Non Finnish (NFE) AF: 0.569 AC: 38676 AN: 67966

Other (OTH) AF: 0.443 AC: 937 AN: 2114

Alfa AF: 0.524 Hom.: 45669

Bravo AF: 0.398

Asia WGS AF: 0.528 AC: 1835 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.15
DANN	Benign	0.47
PhyloP100		-0.81
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: rs2981428; hg19: chr10-123329429;