NM_000141.5:c.624+3070A>C

Variant names:

• chr10-121548220-T-G
• rs7073360
• NM_000141.5:c.624+3070A>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.624+3070A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0787 in 139,976 control chromosomes in the GnomAD database, including 1,118 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 0.079 (1118 hom., cov: 29)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.173
• 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.624+3070A>C		intron_variant	Intron 5 of 17	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.624+3070A>C		intron_variant	Intron 5 of 17	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.624+3070A>C		intron_variant	Intron 5 of 17	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.624+3070A>C		intron_variant	Intron 4 of 16	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.624+3070A>C		intron_variant	Intron 5 of 16	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.357+3070A>C		intron_variant	Intron 4 of 16	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.624+3070A>C		intron_variant	Intron 4 of 14	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.279+3070A>C		intron_variant	Intron 3 of 15	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.357+3070A>C		intron_variant	Intron 4 of 16	2		ENSP00000353262.3
FGFR2	ENST00000604236.5	n.279+3070A>C		intron_variant	Intron 3 of 16	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes AF: 0.0784 AC: 10967 AN: 139904 Hom.: 1105 Cov.: 29

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.0423

Gnomad AMR AF: 0.0781

Gnomad ASJ AF: 0.00476

Gnomad EAS AF: 0.0817

Gnomad SAS AF: 0.00756

Gnomad FIN AF: 0.0330

Gnomad MID AF: 0.00360

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.0584

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

GnomAD4 genome AF: 0.0787 AC: 11019 AN: 139976 Hom.: 1118 Cov.: 29 AF XY: 0.0802 AC XY: 5380 AN XY: 67108

African (AFR) AF: 0.233 AC: 9004 AN: 38686

American (AMR) AF: 0.0790 AC: 1071 AN: 13562

Ashkenazi Jewish (ASJ) AF: 0.00476 AC: 16 AN: 3362

East Asian (EAS) AF: 0.0808 AC: 343 AN: 4246

South Asian (SAS) AF: 0.00782 AC: 32 AN: 4090

European-Finnish (FIN) AF: 0.0330 AC: 252 AN: 7632

Middle Eastern (MID) AF: 0.00400 AC: 1 AN: 250

European-Non Finnish (NFE) AF: 0.00228 AC: 149 AN: 65328

Other (OTH) AF: 0.0586 AC: 114 AN: 1946

Alfa AF: 0.0549 Hom.: 110

Bravo AF: 0.0898

Asia WGS AF: 0.0510 AC: 177 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.7
DANN	Benign	0.50
PhyloP100		-0.17
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: rs7073360; hg19: chr10-123307734; COSMIC: COSV60645485;