chr10-121564448-A-G

Variant names:

• chr10-121564448-A-G
• rs2303568
• NM_022970.4:c.454+54T>C

Variant summary

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

The NM_022970.4(FGFR2):​c.454+54T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,521,000 control chromosomes in the GnomAD database, including 5,241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2639 hom., cov: 32)
  • Exomes 𝑓: 0.018 (2602 hom.)
• Consequence: FGFR2 NM_022970.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.229
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 10-121564448-A-G is Benign according to our data. Variant chr10-121564448-A-G is described in ClinVar as Benign. ClinVar VariationId is 1221381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022970.4. 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.454+54T>C		intron	N/A	NP_075259.4
	FGFR2	NM_000141.5	MANE Select	c.454+54T>C		intron	N/A	NP_000132.3
	FGFR2	NM_001441087.1		c.454+54T>C		intron	N/A	NP_001428016.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	ENST00000457416.7	TSL:1 MANE Plus Clinical	c.454+54T>C		intron	N/A	ENSP00000410294.2
	FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.454+54T>C		intron	N/A	ENSP00000351276.6
	FGFR2	ENST00000369056.5	TSL:1	c.454+54T>C		intron	N/A	ENSP00000358052.1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16661 AN: 151838 Hom.: 2621 Cov.: 32

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0873

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.0734

Gnomad SAS AF: 0.00752

Gnomad FIN AF: 0.0302

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00262

Gnomad OTH AF: 0.0822

GnomAD4 exome AF: 0.0175 AC: 24014 AN: 1369042 Hom.: 2602 Cov.: 22 AF XY: 0.0154 AC XY: 10543 AN XY: 686418

African (AFR) AF: 0.358 AC: 11277 AN: 31534

American (AMR) AF: 0.106 AC: 4728 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.000702 AC: 18 AN: 25638

East Asian (EAS) AF: 0.0729 AC: 2863 AN: 39254

South Asian (SAS) AF: 0.00344 AC: 291 AN: 84476

European-Finnish (FIN) AF: 0.0288 AC: 1503 AN: 52186

Middle Eastern (MID) AF: 0.0222 AC: 117 AN: 5276

European-Non Finnish (NFE) AF: 0.00132 AC: 1357 AN: 1028712

Other (OTH) AF: 0.0324 AC: 1860 AN: 57332

GnomAD4 genome AF: 0.110 AC: 16727 AN: 151958 Hom.: 2639 Cov.: 32 AF XY: 0.109 AC XY: 8132 AN XY: 74274

African (AFR) AF: 0.346 AC: 14296 AN: 41358

American (AMR) AF: 0.0880 AC: 1344 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.0726 AC: 374 AN: 5154

South Asian (SAS) AF: 0.00753 AC: 36 AN: 4782

European-Finnish (FIN) AF: 0.0302 AC: 320 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00262 AC: 178 AN: 67998

Other (OTH) AF: 0.0818 AC: 173 AN: 2114

Alfa AF: 0.0464 Hom.: 207

Bravo AF: 0.126

Asia WGS AF: 0.0570 AC: 199 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	9.7
DANN	Benign	0.63
PhyloP100		-0.23
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: rs2303568; hg19: chr10-123323962; COSMIC: COSV60642648;