8-38429293-C-G

Variant names:

• chr8-38429293-C-G
• rs2304000
• ENST00000484370.5:n.*3G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000484370.5(FGFR1):​n.*3G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 532,752 control chromosomes in the GnomAD database, including 11,540 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3399 hom., cov: 33)
  • Exomes 𝑓: 0.20 (8141 hom.)
• Consequence: FGFR1 ENST00000484370.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0140
• Publications: 15 publications found

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]

FGFR1 Gene-Disease associations (from GenCC):

• encephalocraniocutaneous lipomatosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Hartsfield-Bixler-Demyer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, ClinGen
• hypogonadotropic hypogonadism 2 with or without anosmia

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• osteoglophonic dysplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Pfeiffer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Pfeiffer syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Jackson-Weiss syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated trigonocephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• septooptic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• holoprosencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.358+389G>C		intron_variant	Intron 3 of 17	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000487647.5	n.*3G>C		non_coding_transcript_exon_variant	Exon 2 of 12	1		ENSP00000435254.1
FGFR1	ENST00000487647.5	n.*3G>C		3_prime_UTR_variant	Exon 2 of 12	1		ENSP00000435254.1
FGFR1	ENST00000447712.7	c.358+389G>C		intron_variant	Intron 3 of 17	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.358+389G>C		intron_variant	Intron 3 of 17	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.358+389G>C		intron_variant	Intron 4 of 18	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.358+389G>C		intron_variant	Intron 3 of 17	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.92-858G>C		intron_variant	Intron 2 of 16	1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.92-858G>C		intron_variant	Intron 1 of 15	5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.92-858G>C		intron_variant	Intron 2 of 16	1		ENSP00000327229.6

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30968 AN: 152048 Hom.: 3380 Cov.: 33

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.0991

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.211

GnomAD2 exomes AF: 0.204 AC: 44108 AN: 215888 AF XY: 0.199

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.231

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.314

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.221

Gnomad OTH exome AF: 0.203

GnomAD4 exome AF: 0.202 AC: 76760 AN: 380586 Hom.: 8141 Cov.: 0 AF XY: 0.194 AC XY: 41903 AN XY: 215652

African (AFR) AF: 0.162 AC: 1857 AN: 11478

American (AMR) AF: 0.231 AC: 8091 AN: 35008

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 1857 AN: 12652

East Asian (EAS) AF: 0.319 AC: 4562 AN: 14280

South Asian (SAS) AF: 0.109 AC: 7046 AN: 64504

European-Finnish (FIN) AF: 0.180 AC: 3339 AN: 18500

Middle Eastern (MID) AF: 0.198 AC: 578 AN: 2920

European-Non Finnish (NFE) AF: 0.225 AC: 45656 AN: 203314

Other (OTH) AF: 0.210 AC: 3774 AN: 17930

GnomAD4 genome AF: 0.204 AC: 31035 AN: 152166 Hom.: 3399 Cov.: 33 AF XY: 0.199 AC XY: 14824 AN XY: 74378

African (AFR) AF: 0.160 AC: 6663 AN: 41524

American (AMR) AF: 0.226 AC: 3461 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 529 AN: 3472

East Asian (EAS) AF: 0.310 AC: 1604 AN: 5172

South Asian (SAS) AF: 0.0992 AC: 478 AN: 4818

European-Finnish (FIN) AF: 0.187 AC: 1975 AN: 10586

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15487 AN: 67982

Other (OTH) AF: 0.210 AC: 444 AN: 2114

Alfa AF: 0.199 Hom.: 572

Bravo AF: 0.212

Asia WGS AF: 0.202 AC: 703 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.9
DANN	Benign	0.57
PhyloP100		-0.014
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2304000; hg19: chr8-38286811; COSMIC: COSV58328363; COSMIC: COSV58328363;