rs1047057

Positions:

• chr10-121479598-G-A
• chr10-121479598-G-C
• chr10-121479598-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000141.5(FGFR2):​c.*259C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 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 NM_000141.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.19

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 -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 id is 298991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121479598-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.*259C>T		3_prime_UTR_variant	18/18	ENST00000358487.10	NP_000132.3
FGFR2	NM_022970.4	c.*259C>T		3_prime_UTR_variant	18/18	ENST00000457416.7	NP_075259.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.*259C>T		3_prime_UTR_variant	18/18	1	NM_000141.5	ENSP00000351276	A2
FGFR2	ENST00000457416.7	c.*259C>T		3_prime_UTR_variant	18/18	1	NM_022970.4	ENSP00000410294	P4

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

GnomAD3 exomes AF: 0.555 AC: 85941 AN: 154958 Hom.: 25377 AF XY: 0.555 AC XY: 45461 AN XY: 81928

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 SAS exome AF: 0.597

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

Gnomad4 AFR exome AF: 0.143

Gnomad4 AMR exome AF: 0.732

Gnomad4 ASJ exome AF: 0.561

Gnomad4 EAS exome AF: 0.391

Gnomad4 SAS exome AF: 0.596

Gnomad4 FIN exome AF: 0.501

Gnomad4 NFE exome AF: 0.564

Gnomad4 OTH exome AF: 0.525

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

Gnomad4 AFR AF: 0.157

Gnomad4 AMR AF: 0.633

Gnomad4 ASJ AF: 0.589

Gnomad4 EAS AF: 0.373

Gnomad4 SAS AF: 0.600

Gnomad4 FIN AF: 0.493

Gnomad4 NFE AF: 0.554

Gnomad4 OTH AF: 0.477

Alfa AF: 0.531 Hom.: 35346

Bravo AF: 0.442

Asia WGS AF: 0.476 AC: 1652 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 09, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Crouzon syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Beare-Stevenson cutis gyrata syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Isolated coronal synostosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Craniosynostosis syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Saethre-Chotzen syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Benign	0.65

Splicing

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

Publications

LitVar

Other links and lift over

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