rs3213849

Positions:

• chr8-38468528-G-A
• chr8-38468528-G-C

Variant summary

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

The NM_023110.3(FGFR1):​c.-636C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 228,486 control chromosomes in the GnomAD database, including 14,762 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.34 (9460 hom., cov: 34)
  • Exomes 𝑓: 0.37 (5302 hom.)
• Consequence: FGFR1 NM_023110.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 0.897

Genes affected

FGFR1 (HGNC:3688): (fibroblast growth factor receptor 1) The protein encoded by this gene is a member of the fibroblast growth factor receptor (FGFR) 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 binds both acidic and basic fibroblast growth factors and is involved in limb induction. Mutations in this gene have been associated with Pfeiffer syndrome, Jackson-Weiss syndrome, Antley-Bixler syndrome, osteoglophonic dysplasia, and autosomal dominant Kallmann syndrome 2. Chromosomal aberrations involving this gene are associated with stem cell myeloproliferative disorder and stem cell leukemia lymphoma syndrome. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 8-38468528-G-A is Benign according to our data. Variant chr8-38468528-G-A is described in ClinVar as [Benign]. Clinvar id is 362918.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-38468528-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR1	NM_023110.3	c.-636C>T		5_prime_UTR_variant	1/18	ENST00000447712.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR1	ENST00000447712.7	c.-636C>T		5_prime_UTR_variant	1/18	1	NM_023110.3	P4

Frequencies

GnomAD3 genomes AF: 0.342 AC: 52045 AN: 151984 Hom.: 9450 Cov.: 34

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.350

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.388

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.323

GnomAD4 exome AF: 0.369 AC: 28192 AN: 76392 Hom.: 5302 Cov.: 0 AF XY: 0.374 AC XY: 13187 AN XY: 35234

Gnomad4 AFR exome AF: 0.240

Gnomad4 AMR exome AF: 0.258

Gnomad4 ASJ exome AF: 0.352

Gnomad4 EAS exome AF: 0.308

Gnomad4 SAS exome AF: 0.563

Gnomad4 FIN exome AF: 0.482

Gnomad4 NFE exome AF: 0.398

Gnomad4 OTH exome AF: 0.360

GnomAD4 genome AF: 0.342 AC: 52058 AN: 152094 Hom.: 9460 Cov.: 34 AF XY: 0.345 AC XY: 25644 AN XY: 74348

Gnomad4 AFR AF: 0.229

Gnomad4 AMR AF: 0.277

Gnomad4 ASJ AF: 0.340

Gnomad4 EAS AF: 0.350

Gnomad4 SAS AF: 0.512

Gnomad4 FIN AF: 0.390

Gnomad4 NFE AF: 0.405

Gnomad4 OTH AF: 0.326

Alfa AF: 0.277 Hom.: 922

Bravo AF: 0.323

Asia WGS AF: 0.426 AC: 1475 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

Trigonocephaly 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Hypogonadotropic hypogonadism 2 with or without anosmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Osteoglophonic dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 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	-0.68
CADD	Benign	14
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3213849; hg19: chr8-38326046;