10-121565520-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000141.5(FGFR2):c.294G>A(p.Thr98=) 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:15
• Conservation: PhyloP100: 0.0210

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 196217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121565520-C-T is described in Lovd as [Benign]. Variant chr10-121565520-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1134 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR2	NM_022970.4	c.294G>A	p.Thr98=	synonymous_variant	3/18	ENST00000457416.7
FGFR2	NM_000141.5	c.294G>A	p.Thr98=	synonymous_variant	3/18	ENST00000358487.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR2	ENST00000457416.7	c.294G>A	p.Thr98=	synonymous_variant	3/18	1	NM_022970.4	P4
FGFR2	ENST00000358487.10	c.294G>A	p.Thr98=	synonymous_variant	3/18	1	NM_000141.5	A2

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

GnomAD3 exomes AF: 0.00799 AC: 2010 AN: 251458 Hom.: 19 AF XY: 0.00800 AC XY: 1087 AN XY: 135912

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 SAS exome AF: 0.00385

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

Gnomad4 AFR exome AF: 0.00197

Gnomad4 AMR exome AF: 0.00342

Gnomad4 ASJ exome AF: 0.00264

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00452

Gnomad4 FIN exome AF: 0.0265

Gnomad4 NFE exome AF: 0.00854

Gnomad4 OTH exome AF: 0.00664

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

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00504

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.0265

Gnomad4 NFE AF: 0.00957

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00846 Hom.: 2

Bravo AF: 0.00546

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00894

EpiControl AF: 0.00812

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 31, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 23, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 25, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	FGFR2: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2018	- -

FGFR2-related craniosynostosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Crouzon syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Beare-Stevenson cutis gyrata syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Isolated coronal synostosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Craniosynostosis syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Saethre-Chotzen syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
Cadd	Benign	8.8
Dann	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs1047101; hg19: chr10-123325034; COSMIC: COSV104631726;