rs2915665

Variant names:

• chr8-38429695-G-A
• rs2915665
• NM_023110.3:c.345C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-38429695-G-A
• chr8-38429695-G-C
• chr8-38429695-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_023110.3(FGFR1):​c.345C>T​(p.Ser115Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00701 in 1,568,996 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0072 (51 hom.)
• Consequence: FGFR1 NM_023110.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.858

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 8-38429695-G-A is Benign according to our data. Variant chr8-38429695-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 196513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-38429695-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.858 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00556 (847/152310) while in subpopulation NFE AF= 0.00775 (527/68010). AF 95% confidence interval is 0.0072. There are 3 homozygotes in gnomad4. There are 429 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 SM gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.345C>T	p.Ser115Ser	synonymous_variant	Exon 3 of 18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.345C>T	p.Ser115Ser	synonymous_variant	Exon 3 of 18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.345C>T	p.Ser115Ser	synonymous_variant	Exon 3 of 18	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.345C>T	p.Ser115Ser	synonymous_variant	Exon 4 of 19	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.345C>T	p.Ser115Ser	synonymous_variant	Exon 3 of 18	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.92-1260C>T		intron_variant	Intron 2 of 16	1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.92-1260C>T		intron_variant	Intron 1 of 15	5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.92-1260C>T		intron_variant	Intron 2 of 16	1		ENSP00000327229.6
FGFR1	ENST00000487647.5	n.92-305C>T		intron_variant	Intron 1 of 11	1		ENSP00000435254.1

Frequencies

GnomAD3 genomes AF: 0.00557 AC: 847 AN: 152192 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00775

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00562 AC: 1013 AN: 180288 Hom.: 5 AF XY: 0.00562 AC XY: 539 AN XY: 95948

Gnomad AFR exome AF: 0.00112

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00268

Gnomad FIN exome AF: 0.0186

Gnomad NFE exome AF: 0.00735

Gnomad OTH exome AF: 0.00352

GnomAD4 exome AF: 0.00716 AC: 10146 AN: 1416686 Hom.: 51 Cov.: 31 AF XY: 0.00706 AC XY: 4946 AN XY: 700462

Gnomad4 AFR exome AF: 0.000804

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00205

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00241

Gnomad4 FIN exome AF: 0.0184

Gnomad4 NFE exome AF: 0.00785

Gnomad4 OTH exome AF: 0.00592

GnomAD4 genome AF: 0.00556 AC: 847 AN: 152310 Hom.: 3 Cov.: 33 AF XY: 0.00576 AC XY: 429 AN XY: 74472

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0195

Gnomad4 NFE AF: 0.00775

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00617 Hom.: 2

Bravo AF: 0.00412

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FGFR1: BP4, BS2 -

Jul 02, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 23, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

Feb 05, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

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. -

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. -

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

- -

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	-0.28
CADD	Benign	15
DANN	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs2915665; hg19: chr8-38287213;