rs4647904

Variant names:

• chr8-38414029-G-A
• rs4647904
• NM_023110.3:c.2187-6C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-38414029-G-A
• chr8-38414029-G-C
• chr8-38414029-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_023110.3(FGFR1):​c.2187-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,613,888 control chromosomes in the GnomAD database, including 391 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (38 hom., cov: 33)
  • Exomes 𝑓: 0.019 (353 hom.)
• Consequence: FGFR1 NM_023110.3 splice_region, intron
• Scores: Splicing: ADA: 0.0005381
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.139

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=-0.86).
• BP6: Variant 8-38414029-G-A is Benign according to our data. Variant chr8-38414029-G-A is described in ClinVar as [Benign]. Clinvar id is 194786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-38414029-G-A is described in Lovd as [Benign]. Variant chr8-38414029-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0145 (2213/152250) while in subpopulation NFE AF= 0.0217 (1472/67990). AF 95% confidence interval is 0.0207. There are 38 homozygotes in gnomad4. There are 1081 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 38 SM gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.2187-6C>T		splice_region_variant, intron_variant	Intron 16 of 17	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.2187-6C>T		splice_region_variant, intron_variant	Intron 16 of 17	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.2181-6C>T		splice_region_variant, intron_variant	Intron 16 of 17	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.2181-6C>T		splice_region_variant, intron_variant	Intron 17 of 18	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.2181-6C>T		splice_region_variant, intron_variant	Intron 16 of 17	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.1920-6C>T		splice_region_variant, intron_variant	Intron 15 of 16	1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.1920-6C>T		splice_region_variant, intron_variant	Intron 14 of 15	5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.1914-6C>T		splice_region_variant, intron_variant	Intron 15 of 16	1		ENSP00000327229.6

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2213 AN: 152132 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00850

Gnomad FIN AF: 0.0413

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0216

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0156 AC: 3895 AN: 249902 Hom.: 56 AF XY: 0.0158 AC XY: 2137 AN XY: 135320

Gnomad AFR exome AF: 0.00276

Gnomad AMR exome AF: 0.00328

Gnomad ASJ exome AF: 0.00984

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.0106

Gnomad FIN exome AF: 0.0401

Gnomad NFE exome AF: 0.0209

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.0194 AC: 28407 AN: 1461638 Hom.: 353 Cov.: 32 AF XY: 0.0192 AC XY: 13982 AN XY: 727110

Gnomad4 AFR exome AF: 0.00245

Gnomad4 AMR exome AF: 0.00367

Gnomad4 ASJ exome AF: 0.0114

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0107

Gnomad4 FIN exome AF: 0.0373

Gnomad4 NFE exome AF: 0.0215

Gnomad4 OTH exome AF: 0.0170

GnomAD4 genome AF: 0.0145 AC: 2213 AN: 152250 Hom.: 38 Cov.: 33 AF XY: 0.0145 AC XY: 1081 AN XY: 74438

Gnomad4 AFR AF: 0.00315

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00871

Gnomad4 FIN AF: 0.0413

Gnomad4 NFE AF: 0.0217

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.0179 Hom.: 16

Bravo AF: 0.0116

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0190

EpiControl AF: 0.0176

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Jun 05, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 14, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:5

Jan 16, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27884173, 23348397) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 11, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FGFR1: BP4, BS1, BS2 -

Trigonocephaly 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hypogonadotropic hypogonadism 2 with or without anosmia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteoglophonic dysplasia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Craniosynostosis syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.74
DANN	Uncertain	0.99
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00054
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: rs4647904; hg19: chr8-38271547; COSMIC: COSV99050068; COSMIC: COSV99050068;