rs1801043

Variant names:

• chr10-121538071-C-T
• rs1801043
• ENST00000359354.6:c.*323G>A

Variant summary

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

The ENST00000359354.6(FGFR2):​c.*323G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0743 in 483,658 control chromosomes in the GnomAD database, including 1,733 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 0.067 (491 hom., cov: 33)
  • Exomes 𝑓: 0.078 (1242 hom.)
• Consequence: FGFR2 ENST00000359354.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.911
• Publications: 4 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 (AMR) allele frequency at 95% confidence interval = 0.0909 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.748+521G>A		intron_variant	Intron 6 of 17	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.748+521G>A		intron_variant	Intron 6 of 17	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.748+521G>A		intron_variant	Intron 6 of 17	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.748+521G>A		intron_variant	Intron 5 of 16	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.748+521G>A		intron_variant	Intron 6 of 16	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.481+521G>A		intron_variant	Intron 5 of 16	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.748+521G>A		intron_variant	Intron 5 of 14	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.403+521G>A		intron_variant	Intron 4 of 15	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.481+521G>A		intron_variant	Intron 5 of 16	2		ENSP00000353262.3
FGFR2	ENST00000604236.5	n.403+521G>A		intron_variant	Intron 4 of 16	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes AF: 0.0670 AC: 10189 AN: 152098 Hom.: 490 Cov.: 33

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0930

Gnomad ASJ AF: 0.0712

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0358

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0929

Gnomad OTH AF: 0.0764

GnomAD4 exome AF: 0.0777 AC: 25754 AN: 331442 Hom.: 1242 Cov.: 0 AF XY: 0.0757 AC XY: 13085 AN XY: 172908

African (AFR) AF: 0.0156 AC: 161 AN: 10322

American (AMR) AF: 0.0973 AC: 1109 AN: 11400

Ashkenazi Jewish (ASJ) AF: 0.0798 AC: 863 AN: 10814

East Asian (EAS) AF: 0.000175 AC: 4 AN: 22806

South Asian (SAS) AF: 0.0417 AC: 1308 AN: 31336

European-Finnish (FIN) AF: 0.103 AC: 2017 AN: 19546

Middle Eastern (MID) AF: 0.0654 AC: 97 AN: 1484

European-Non Finnish (NFE) AF: 0.0920 AC: 18760 AN: 203956

Other (OTH) AF: 0.0726 AC: 1435 AN: 19778

GnomAD4 genome AF: 0.0669 AC: 10189 AN: 152216 Hom.: 491 Cov.: 33 AF XY: 0.0677 AC XY: 5041 AN XY: 74406

African (AFR) AF: 0.0153 AC: 635 AN: 41548

American (AMR) AF: 0.0932 AC: 1425 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0712 AC: 247 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0359 AC: 173 AN: 4822

European-Finnish (FIN) AF: 0.106 AC: 1123 AN: 10598

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0928 AC: 6313 AN: 67992

Other (OTH) AF: 0.0756 AC: 160 AN: 2116

Alfa AF: 0.0894 Hom.: 388

Bravo AF: 0.0638

Asia WGS AF: 0.0230 AC: 79 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	1.5
DANN	Benign	0.38
PhyloP100		-0.91
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: rs1801043; hg19: chr10-123297585;