rs17182463

Variant names:

• chr8-38413633-G-A
• rs17182463
• NM_023110.3:c.2464C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-38413633-G-A
• chr8-38413633-G-C
• chr8-38413633-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS1

The NM_023110.3(FGFR1):​c.2464C>T​(p.Arg822Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000327 in 1,608,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R822H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: FGFR1 NM_023110.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 9.60
• Publications: 22 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 -6 ACMG points.

• PP2: Missense variant in the FGFR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 93 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 2.4852 (below the threshold of 3.09). Trascript score misZ: 4.2642 (above the threshold of 3.09). GenCC associations: The gene is linked to Hartsfield-Bixler-Demyer syndrome, Pfeiffer syndrome type 1, encephalocraniocutaneous lipomatosis, hypogonadotropic hypogonadism 2 with or without anosmia, osteoglophonic dysplasia, isolated trigonocephaly, septooptic dysplasia, Pfeiffer syndrome, tooth agenesis, hypogonadotropic hypogonadism, Kallmann syndrome, holoprosencephaly, Jackson-Weiss syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13991779).
• BP6: Variant 8-38413633-G-A is Benign according to our data. Variant chr8-38413633-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 536195.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000263 (40/152220) while in subpopulation AMR AF = 0.000393 (6/15286). AF 95% confidence interval is 0.000243. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR1	NM_023110.3	MANE Select	c.2464C>T	p.Arg822Cys	missense	Exon 18 of 18	NP_075598.2
	FGFR1	NM_001174067.2		c.2557C>T	p.Arg853Cys	missense	Exon 19 of 19	NP_001167538.1
	FGFR1	NM_001174063.2		c.2458C>T	p.Arg820Cys	missense	Exon 18 of 18	NP_001167534.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR1	ENST00000447712.7	TSL:1 MANE Select	c.2464C>T	p.Arg822Cys	missense	Exon 18 of 18	ENSP00000400162.2
	FGFR1	ENST00000397091.9	TSL:1	c.2458C>T	p.Arg820Cys	missense	Exon 18 of 18	ENSP00000380280.5
	FGFR1	ENST00000397108.8	TSL:1	c.2458C>T	p.Arg820Cys	missense	Exon 19 of 19	ENSP00000380297.4

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000265 AC: 63 AN: 237824 AF XY: 0.000271

Gnomad AFR exome AF: 0.000138

Gnomad AMR exome AF: 0.000899

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000260

Gnomad OTH exome AF: 0.000528

GnomAD4 exome AF: 0.000334 AC: 486 AN: 1456680 Hom.: 0 Cov.: 32 AF XY: 0.000348 AC XY: 252 AN XY: 724118

African (AFR) AF: 0.0000897 AC: 3 AN: 33434

American (AMR) AF: 0.000843 AC: 37 AN: 43872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25830

East Asian (EAS) AF: 0.00 AC: 0 AN: 39532

South Asian (SAS) AF: 0.00 AC: 0 AN: 85366

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53062

Middle Eastern (MID) AF: 0.000195 AC: 1 AN: 5120

European-Non Finnish (NFE) AF: 0.000385 AC: 427 AN: 1110352

Other (OTH) AF: 0.000299 AC: 18 AN: 60112

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17 AN XY: 74354

African (AFR) AF: 0.000145 AC: 6 AN: 41452

American (AMR) AF: 0.000393 AC: 6 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68036

Other (OTH) AF: 0.00143 AC: 3 AN: 2094

Alfa AF: 0.000300 Hom.: 0

Bravo AF: 0.000385

ESP6500AA AF: 0.000478 AC: 2

ESP6500EA AF: 0.000238 AC: 2

ExAC AF: 0.000173 AC: 21

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypogonadotropic hypogonadism 2 with or without anosmia Uncertain:1 Benign:1

May 04, 2023

Reproductive Endocrine Unit, Massachusetts General Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

The variant has been classified as VUS based on the variant meeting the following ACMG Criteria: BS3.

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Pfeiffer syndrome;C0406612:Encephalocraniocutaneous lipomatosis Uncertain:1

Jul 21, 2025

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

An FGFR1 c.2464C>T (p.Arg822Cys) variant was identified at a near heterozygous allelic fraction of 44.8%, a frequency which may be consistent with it being of germline origin. This variant has been reported in one individual affected with Kallmann's syndrome and, to our knowledge, it has not been reported in Kaposiform hemangioendothelioma ((Dodé C et al., PMID: 18985070). This variant has been reported in the ClinVar database in a germline state as likely benign/benign by four submitters and a variant of uncertain significance by one submitter (ClinVar ID 536195). The highest population minor allele frequency in the population database genome aggregation database (v.4.1.0) is 0.07% in the Admixed American population. Computational predictors are uncertain as to the impact of this variant on FGFR1 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.

Trigonocephaly 1 Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

FGFR1-related disorder Benign:1

Oct 31, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

not provided Benign:1

Jun 21, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: Neocleous2019[Abstract], 32982993, 27535533, 29419413, 18985070, 17154279, 23329143)

Osteoglophonic dysplasia Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Pfeiffer syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia Benign:1

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Craniosynostosis syndrome Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.2	L
PhyloP100		9.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.51	N
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.48
MVP		0.84
MPC		2.4
ClinPred		0.11	T
GERP RS		5.7
Varity_R		0.36
gMVP		0.60
Mutation Taster		=50/50

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: rs17182463; hg19: chr8-38271151; COSMIC: COSV100247550; COSMIC: COSV100247550;