rs4647905

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr8-38415024-C-A
• chr8-38415024-C-G
• chr8-38415024-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001174067.2(FGFR1):​c.1948-123G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000225 in 578,710 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: FGFR1 NM_001174067.2 intron
• Clinical Significance: Not reported in ClinVar
• 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: 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001174067.2. 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>T		intron	N/A	NP_075598.2
	FGFR1	NM_001174067.2		c.1948-123G>T		intron	N/A	NP_001167538.1
	FGFR1	NM_001354367.2		c.1849-123G>T		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>T		intron	N/A	ENSP00000400162.2
	FGFR1	ENST00000425967.8	TSL:1	c.1843-123G>T		intron	N/A	ENSP00000393312.4
	FGFR1	ENST00000397091.9	TSL:1	c.1849-123G>T		intron	N/A	ENSP00000380280.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000225 AC: 13 AN: 578710 Hom.: 0 AF XY: 0.0000296 AC XY: 9 AN XY: 303656

African (AFR) AF: 0.00 AC: 0 AN: 15292

American (AMR) AF: 0.00 AC: 0 AN: 25318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16100

East Asian (EAS) AF: 0.000186 AC: 6 AN: 32220

South Asian (SAS) AF: 0.00 AC: 0 AN: 54500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2250

European-Non Finnish (NFE) AF: 0.0000190 AC: 7 AN: 368730

Other (OTH) AF: 0.00 AC: 0 AN: 30414

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 71

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.2
DANN	Benign	0.53
PhyloP100		-0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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;