rs1047101

Variant names:

• chr10-121565520-C-T
• rs1047101
• NM_022970.4:c.294G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-121565520-C-T
• chr10-121565520-C-A
• chr10-121565520-C-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000141.5(FGFR2):​c.294G>A​(p.Thr98Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00815 in 1,614,202 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (92 hom.)
• Consequence: FGFR2 NM_000141.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.0210
• Publications: 8 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: ClinGen, Genomics England PanelApp, G2P, Orphanet
• Beare-Stevenson cutis gyrata syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, ClinGen, G2P
• bent bone dysplasia syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Crouzon syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Ambry Genetics, G2P
• Jackson-Weiss syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• LADD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Pfeiffer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
• Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
• familial scaphocephaly syndrome, McGillivray type

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Saethre-Chotzen syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Antley-Bixler syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LADD syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 10-121565520-C-T is Benign according to our data. Variant chr10-121565520-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00744 (1133/152312) while in subpopulation NFE AF = 0.00957 (651/68026). AF 95% confidence interval is 0.00896. There are 3 homozygotes in GnomAd4. There are 617 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1133 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000141.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	NM_022970.4	MANE Plus Clinical	c.294G>A	p.Thr98Thr	synonymous	Exon 3 of 18	NP_075259.4	P21802-3
	FGFR2	NM_000141.5	MANE Select	c.294G>A	p.Thr98Thr	synonymous	Exon 3 of 18	NP_000132.3	P21802-1
	FGFR2	NM_001441087.1		c.294G>A	p.Thr98Thr	synonymous	Exon 3 of 18	NP_001428016.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	ENST00000457416.7	TSL:1 MANE Plus Clinical	c.294G>A	p.Thr98Thr	synonymous	Exon 3 of 18	ENSP00000410294.2	P21802-3
	FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.294G>A	p.Thr98Thr	synonymous	Exon 3 of 18	ENSP00000351276.6	P21802-1
	FGFR2	ENST00000369056.5	TSL:1	c.294G>A	p.Thr98Thr	synonymous	Exon 2 of 17	ENSP00000358052.1	P21802-17

Frequencies

GnomAD3 genomes AF: 0.00745 AC: 1134 AN: 152194 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0265

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00957

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00799 AC: 2010 AN: 251458 AF XY: 0.00800

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0248

Gnomad NFE exome AF: 0.00984

Gnomad OTH exome AF: 0.00961

GnomAD4 exome AF: 0.00822 AC: 12023 AN: 1461890 Hom.: 92 Cov.: 31 AF XY: 0.00815 AC XY: 5927 AN XY: 727248

African (AFR) AF: 0.00197 AC: 66 AN: 33480

American (AMR) AF: 0.00342 AC: 153 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00264 AC: 69 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00452 AC: 390 AN: 86258

European-Finnish (FIN) AF: 0.0265 AC: 1415 AN: 53418

Middle Eastern (MID) AF: 0.00589 AC: 34 AN: 5768

European-Non Finnish (NFE) AF: 0.00854 AC: 9494 AN: 1112010

Other (OTH) AF: 0.00664 AC: 401 AN: 60396

GnomAD4 genome AF: 0.00744 AC: 1133 AN: 152312 Hom.: 3 Cov.: 32 AF XY: 0.00828 AC XY: 617 AN XY: 74476

African (AFR) AF: 0.00147 AC: 61 AN: 41586

American (AMR) AF: 0.00504 AC: 77 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00291 AC: 14 AN: 4816

European-Finnish (FIN) AF: 0.0265 AC: 281 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00957 AC: 651 AN: 68026

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00863 Hom.: 4

Bravo AF: 0.00546

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00894

EpiControl AF: 0.00812

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	1	Beare-Stevenson cutis gyrata syndrome (1)
-	-	1	Craniosynostosis syndrome (1)
-	-	1	Crouzon syndrome (1)
-	-	1	FGFR2-related craniosynostosis (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	-0.29
CADD	Benign	8.8
DANN	Benign	0.65
PhyloP100		0.021
Mutation Taster		=99/1	polymorphism

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: rs1047101; hg19: chr10-123325034;