chr8-38468528-G-A

Variant names:

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

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 VariationId 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.

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.-636C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	NP_075598.2
	FGFR1	NM_023110.3	MANE Select	c.-636C>T		5_prime_UTR	Exon 1 of 18	NP_075598.2
	FGFR1	NM_001354367.2		c.-636C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	NP_001341296.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR1	ENST00000447712.7	TSL:1 MANE Select	c.-636C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	ENSP00000400162.2
	FGFR1	ENST00000397091.9	TSL:1	c.-636C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	ENSP00000380280.5
	FGFR1	ENST00000335922.9	TSL:1	c.-728C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 19	ENSP00000337247.5

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Craniosynostosis syndrome (1)
-	-	1	Hypogonadotropic hypogonadism 2 with or without anosmia (1)
-	-	1	not provided (1)
-	-	1	Osteoglophonic dysplasia (1)
-	-	1	Trigonocephaly 1 (1)

Computational scores

Source: dbNSFP v4.9

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;