rs1047111

chr10-121598047-C-Gchr10-121598047-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000141.5(FGFR2):c.-236G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0785 in 397,856 control chromosomes in the GnomAD database, including 2,322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.099 (1217 hom., cov: 34)
  • Exomes 𝑓: 0.066 (1105 hom.)
• Consequence: FGFR2 NM_000141.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:5
• Conservation: PhyloP100: -2.40

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 10-121598047-C-G is Benign according to our data. Variant chr10-121598047-C-G is described in ClinVar as [Benign]. Clinvar id is 299018.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR2	NM_000141.5	c.-236G>C		5_prime_UTR_variant	1/18	ENST00000358487.10
FGFR2	NM_022970.4	c.-236G>C		5_prime_UTR_variant	1/18	ENST00000457416.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR2	ENST00000358487.10	c.-236G>C		5_prime_UTR_variant	1/18	1	NM_000141.5	A2
FGFR2	ENST00000457416.7	c.-236G>C		5_prime_UTR_variant	1/18	1	NM_022970.4	P4

Frequencies

GnomAD3 genomes AF: 0.0983 AC: 14952 AN: 152078 Hom.: 1211 Cov.: 34

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.0689

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0302

Gnomad OTH AF: 0.0793

GnomAD4 exome AF: 0.0661 AC: 16245 AN: 245658 Hom.: 1105 Cov.: 0 AF XY: 0.0627 AC XY: 7802 AN XY: 124520

Gnomad4 AFR exome AF: 0.176

Gnomad4 AMR exome AF: 0.192

Gnomad4 ASJ exome AF: 0.0156

Gnomad4 EAS exome AF: 0.222

Gnomad4 SAS exome AF: 0.0598

Gnomad4 FIN exome AF: 0.101

Gnomad4 NFE exome AF: 0.0300

Gnomad4 OTH exome AF: 0.0793

GnomAD4 genome AF: 0.0986 AC: 15000 AN: 152198 Hom.: 1217 Cov.: 34 AF XY: 0.103 AC XY: 7698 AN XY: 74386

Gnomad4 AFR AF: 0.178

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.263

Gnomad4 SAS AF: 0.0689

Gnomad4 FIN AF: 0.120

Gnomad4 NFE AF: 0.0302

Gnomad4 OTH AF: 0.0803

Alfa AF: 0.00183 Hom.: 33527

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.75
Cadd	Benign	1.1
Dann	Benign	0.82

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: rs1047111; hg19: chr10-123357561;