NM_023110.3:c.1855-123G>C

Variant names:

• chr8-38415024-C-G
• rs4647905
• NM_023110.3:c.1855-123G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_023110.3(FGFR1):​c.1855-123G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 730,200 control chromosomes in the GnomAD database, including 15,996 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.20 (3241 hom., cov: 32)
  • Exomes 𝑓: 0.20 (12755 hom.)
• Consequence: FGFR1 NM_023110.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.167
• Publications: 12 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: G2P, Ambry Genetics, Orphanet, ClinGen
• hypogonadotropic hypogonadism 2 with or without anosmia

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

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

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

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 8-38415024-C-G is Benign according to our data. Variant chr8-38415024-C-G is described in ClinVar as Benign. ClinVar VariationId is 1292696.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023110.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR1	NM_023110.3	MANE Select	c.1855-123G>C		intron	N/A	NP_075598.2	P11362-1
	FGFR1	NM_001174067.2		c.1948-123G>C		intron	N/A	NP_001167538.1	P11362-21
	FGFR1	NM_001354367.2		c.1849-123G>C		intron	N/A	NP_001341296.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR1	ENST00000447712.7	TSL:1 MANE Select	c.1855-123G>C		intron	N/A	ENSP00000400162.2	P11362-1
	FGFR1	ENST00000425967.8	TSL:1	c.1843-123G>C		intron	N/A	ENSP00000393312.4	A0A8I3B1S4
	FGFR1	ENST00000397091.9	TSL:1	c.1849-123G>C		intron	N/A	ENSP00000380280.5	P11362-7

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30336 AN: 151954 Hom.: 3232 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.204

GnomAD4 exome AF: 0.203 AC: 117351 AN: 578128 Hom.: 12755 AF XY: 0.198 AC XY: 60163 AN XY: 303374

African (AFR) AF: 0.154 AC: 2357 AN: 15284

American (AMR) AF: 0.219 AC: 5540 AN: 25300

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 2235 AN: 16088

East Asian (EAS) AF: 0.313 AC: 10076 AN: 32200

South Asian (SAS) AF: 0.112 AC: 6089 AN: 54478

European-Finnish (FIN) AF: 0.175 AC: 5911 AN: 33860

Middle Eastern (MID) AF: 0.162 AC: 365 AN: 2250

European-Non Finnish (NFE) AF: 0.214 AC: 78682 AN: 368282

Other (OTH) AF: 0.201 AC: 6096 AN: 30386

GnomAD4 genome AF: 0.200 AC: 30376 AN: 152072 Hom.: 3241 Cov.: 32 AF XY: 0.195 AC XY: 14524 AN XY: 74368

African (AFR) AF: 0.166 AC: 6890 AN: 41466

American (AMR) AF: 0.218 AC: 3328 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 477 AN: 3466

East Asian (EAS) AF: 0.305 AC: 1572 AN: 5158

South Asian (SAS) AF: 0.106 AC: 512 AN: 4822

European-Finnish (FIN) AF: 0.183 AC: 1936 AN: 10600

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14846 AN: 67958

Other (OTH) AF: 0.202 AC: 427 AN: 2110

Alfa AF: 0.0566 Hom.: 71

Bravo AF: 0.208

Asia WGS AF: 0.195 AC: 679 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.1
DANN	Benign	0.44
PhyloP100		-0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4647905; hg19: chr8-38272542; COSMIC: COSV100247492;