ENST00000604236.5:n.*1772C>T

Variant names:

• chr10-121479598-G-A
• rs1047057
• ENST00000604236.5:n.*1772C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000604236.5(FGFR2):​n.*1772C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 1,550,826 control chromosomes in the GnomAD database, including 235,727 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (17607 hom., cov: 33)
  • Exomes 𝑓: 0.55 (218120 hom.)
• Consequence: FGFR2 ENST00000604236.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.19
• Publications: 41 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 10-121479598-G-A is Benign according to our data. Variant chr10-121479598-G-A is described in ClinVar as Benign. ClinVar VariationId is 298991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000604236.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	NM_022970.4	MANE Plus Clinical	c.*259C>T		3_prime_UTR	Exon 18 of 18	NP_075259.4
	FGFR2	NM_000141.5	MANE Select	c.*259C>T		3_prime_UTR	Exon 18 of 18	NP_000132.3
	FGFR2	NM_001144915.2		c.2107C>T	p.Leu703Leu	synonymous	Exon 17 of 17	NP_001138387.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	ENST00000604236.5	TSL:1	n.*1772C>T		non_coding_transcript_exon	Exon 17 of 17	ENSP00000474109.1
	FGFR2	ENST00000457416.7	TSL:1 MANE Plus Clinical	c.*259C>T		3_prime_UTR	Exon 18 of 18	ENSP00000410294.2
	FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.*259C>T		3_prime_UTR	Exon 18 of 18	ENSP00000351276.6

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67496 AN: 151966 Hom.: 17592 Cov.: 33

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.633

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.493

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.554

Gnomad OTH AF: 0.479

GnomAD2 exomes AF: 0.555 AC: 85941 AN: 154958 AF XY: 0.555

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.750

Gnomad ASJ exome AF: 0.563

Gnomad EAS exome AF: 0.380

Gnomad FIN exome AF: 0.501

Gnomad NFE exome AF: 0.557

Gnomad OTH exome AF: 0.559

GnomAD4 exome AF: 0.552 AC: 772464 AN: 1398742 Hom.: 218120 Cov.: 42 AF XY: 0.554 AC XY: 381978 AN XY: 689824

African (AFR) AF: 0.143 AC: 4528 AN: 31568

American (AMR) AF: 0.732 AC: 26118 AN: 35664

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 14122 AN: 25172

East Asian (EAS) AF: 0.391 AC: 13964 AN: 35720

South Asian (SAS) AF: 0.596 AC: 47204 AN: 79180

European-Finnish (FIN) AF: 0.501 AC: 24692 AN: 49272

Middle Eastern (MID) AF: 0.480 AC: 2735 AN: 5696

European-Non Finnish (NFE) AF: 0.564 AC: 608675 AN: 1078512

Other (OTH) AF: 0.525 AC: 30426 AN: 57958

GnomAD4 genome AF: 0.444 AC: 67522 AN: 152084 Hom.: 17607 Cov.: 33 AF XY: 0.448 AC XY: 33284 AN XY: 74344

African (AFR) AF: 0.157 AC: 6506 AN: 41500

American (AMR) AF: 0.633 AC: 9671 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 2039 AN: 3464

East Asian (EAS) AF: 0.373 AC: 1931 AN: 5180

South Asian (SAS) AF: 0.600 AC: 2888 AN: 4812

European-Finnish (FIN) AF: 0.493 AC: 5204 AN: 10566

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.554 AC: 37681 AN: 67980

Other (OTH) AF: 0.477 AC: 1008 AN: 2112

Alfa AF: 0.525 Hom.: 42631

Bravo AF: 0.442

Asia WGS AF: 0.476 AC: 1652 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Beare-Stevenson cutis gyrata syndrome (1)
-	-	1	Craniosynostosis syndrome (1)
-	-	1	Crouzon syndrome (1)
-	-	1	Isolated Coronal Synostosis (1)
-	-	1	Saethre-Chotzen syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Benign	0.65
PhyloP100		3.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1047057; hg19: chr10-123239112; COSMIC: COSV60638447; COSMIC: COSV60638447;