rs3213849

Variant names:

• chr8-38468528-G-A
• rs3213849
• NM_023110.3:c.-636C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-38468528-G-A
• chr8-38468528-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_023110.3(FGFR1):​c.-636C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 228,486 control chromosomes in the GnomAD database, including 14,762 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9460 hom., cov: 34)
  • Exomes 𝑓: 0.37 (5302 hom.)
• Consequence: FGFR1 NM_023110.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.897
• Publications: 11 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

ENSG00000305763 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 8-38468528-G-A is Benign according to our data. Variant chr8-38468528-G-A is described in ClinVar as [Benign]. Clinvar id is 362918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.-636C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 18	ENST00000447712.7	NP_075598.2
FGFR1	NM_023110.3	c.-636C>T		5_prime_UTR_variant	Exon 1 of 18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.-636C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.-636C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 18	1		ENSP00000380280.5
FGFR1	ENST00000356207.9	c.-636C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 17	1		ENSP00000348537.5
FGFR1	ENST00000326324.10	c.-636C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 17	1		ENSP00000327229.6
FGFR1	ENST00000447712.7	c.-636C>T		5_prime_UTR_variant	Exon 1 of 18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.-636C>T		5_prime_UTR_variant	Exon 1 of 18	1		ENSP00000380280.5
FGFR1	ENST00000356207.9	c.-636C>T		5_prime_UTR_variant	Exon 1 of 17	1		ENSP00000348537.5
FGFR1	ENST00000326324.10	c.-636C>T		5_prime_UTR_variant	Exon 1 of 17	1		ENSP00000327229.6

Frequencies

GnomAD3 genomes AF: 0.342 AC: 52045 AN: 151984 Hom.: 9450 Cov.: 34

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.350

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.388

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.323

GnomAD4 exome AF: 0.369 AC: 28192 AN: 76392 Hom.: 5302 Cov.: 0 AF XY: 0.374 AC XY: 13187 AN XY: 35234

African (AFR) AF: 0.240 AC: 862 AN: 3592

American (AMR) AF: 0.258 AC: 594 AN: 2304

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 1700 AN: 4834

East Asian (EAS) AF: 0.308 AC: 3447 AN: 11182

South Asian (SAS) AF: 0.563 AC: 376 AN: 668

European-Finnish (FIN) AF: 0.482 AC: 27 AN: 56

Middle Eastern (MID) AF: 0.434 AC: 203 AN: 468

European-Non Finnish (NFE) AF: 0.398 AC: 18694 AN: 46922

Other (OTH) AF: 0.360 AC: 2289 AN: 6366

GnomAD4 genome AF: 0.342 AC: 52058 AN: 152094 Hom.: 9460 Cov.: 34 AF XY: 0.345 AC XY: 25644 AN XY: 74348

African (AFR) AF: 0.229 AC: 9495 AN: 41528

American (AMR) AF: 0.277 AC: 4239 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1180 AN: 3470

East Asian (EAS) AF: 0.350 AC: 1801 AN: 5148

South Asian (SAS) AF: 0.512 AC: 2474 AN: 4828

European-Finnish (FIN) AF: 0.390 AC: 4130 AN: 10584

Middle Eastern (MID) AF: 0.387 AC: 113 AN: 292

European-Non Finnish (NFE) AF: 0.405 AC: 27542 AN: 67934

Other (OTH) AF: 0.326 AC: 688 AN: 2112

Alfa AF: 0.277 Hom.: 922

Bravo AF: 0.323

Asia WGS AF: 0.426 AC: 1475 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.68
CADD	Benign	14
DANN	Benign	0.92
PhyloP100		0.90
PromoterAI		0.054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

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: rs3213849; hg19: chr8-38326046;