8-38428707-G-A

Position:

• chr8-38428707-G-A

Variant summary

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

The NM_023110.3(FGFR1):​c.359-272C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 489,844 control chromosomes in the GnomAD database, including 11,143 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2854 hom., cov: 32)
  • Exomes 𝑓: 0.21 (8289 hom.)
• Consequence: FGFR1 NM_023110.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.533

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-38428707-G-A is Benign according to our data. Variant chr8-38428707-G-A is described in ClinVar as [Benign]. Clinvar id is 1231058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.359-272C>T		intron_variant		ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.359-272C>T		intron_variant		1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.359-272C>T		intron_variant		1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.359-272C>T		intron_variant		1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.359-272C>T		intron_variant		2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.92-272C>T		intron_variant		1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.92-272C>T		intron_variant		5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.92-272C>T		intron_variant		1		ENSP00000327229.6
FGFR1	ENST00000487647.5	n.*50-272C>T		intron_variant		1		ENSP00000435254.1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25894 AN: 152054 Hom.: 2850 Cov.: 32

Gnomad AFR AF: 0.0425

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.0949

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.189

GnomAD4 exome AF: 0.211 AC: 71315 AN: 337672 Hom.: 8289 Cov.: 0 AF XY: 0.211 AC XY: 37610 AN XY: 178082

Gnomad4 AFR exome AF: 0.0378

Gnomad4 AMR exome AF: 0.332

Gnomad4 ASJ exome AF: 0.298

Gnomad4 EAS exome AF: 0.0846

Gnomad4 SAS exome AF: 0.217

Gnomad4 FIN exome AF: 0.211

Gnomad4 NFE exome AF: 0.219

Gnomad4 OTH exome AF: 0.218

GnomAD4 genome AF: 0.170 AC: 25901 AN: 152172 Hom.: 2854 Cov.: 32 AF XY: 0.173 AC XY: 12855 AN XY: 74396

Gnomad4 AFR AF: 0.0424

Gnomad4 AMR AF: 0.276

Gnomad4 ASJ AF: 0.315

Gnomad4 EAS AF: 0.0949

Gnomad4 SAS AF: 0.215

Gnomad4 FIN AF: 0.199

Gnomad4 NFE AF: 0.215

Gnomad4 OTH AF: 0.189

Alfa AF: 0.218 Hom.: 5625

Bravo AF: 0.174

Asia WGS AF: 0.160 AC: 562 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.7
DANN	Benign	0.70

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: rs2288696; hg19: chr8-38286225;