rs2978073

Variant names:

• chr8-38438024-G-A
• rs2978073
• NM_023110.3:c.92-8076C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_023110.3(FGFR1):​c.92-8076C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0898 in 152,156 control chromosomes in the GnomAD database, including 959 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.090 (959 hom., cov: 32)
• Consequence: FGFR1 NM_023110.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• Publications: 9 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.92-8076C>T		intron_variant	Intron 2 of 17	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.92-8076C>T		intron_variant	Intron 2 of 17	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.92-8076C>T		intron_variant	Intron 2 of 17	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.92-8076C>T		intron_variant	Intron 3 of 18	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.92-8076C>T		intron_variant	Intron 2 of 17	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.92-9589C>T		intron_variant	Intron 2 of 16	1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.92-9589C>T		intron_variant	Intron 1 of 15	5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.92-9589C>T		intron_variant	Intron 2 of 16	1		ENSP00000327229.6
FGFR1	ENST00000487647.5	n.92-8634C>T		intron_variant	Intron 1 of 11	1		ENSP00000435254.1

Frequencies

GnomAD3 genomes AF: 0.0898 AC: 13656 AN: 152038 Hom.: 957 Cov.: 32

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0825

Gnomad ASJ AF: 0.0398

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0670

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0898 AC: 13662 AN: 152156 Hom.: 959 Cov.: 32 AF XY: 0.0979 AC XY: 7276 AN XY: 74356

African (AFR) AF: 0.0170 AC: 706 AN: 41520

American (AMR) AF: 0.0825 AC: 1261 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0398 AC: 138 AN: 3466

East Asian (EAS) AF: 0.304 AC: 1565 AN: 5150

South Asian (SAS) AF: 0.183 AC: 882 AN: 4822

European-Finnish (FIN) AF: 0.187 AC: 1975 AN: 10576

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6947 AN: 68018

Other (OTH) AF: 0.0706 AC: 149 AN: 2110

Alfa AF: 0.0983 Hom.: 958

Bravo AF: 0.0748

Asia WGS AF: 0.212 AC: 738 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	9.1
DANN	Benign	0.49
PhyloP100		1.1
Mutation Taster		=100/0	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: rs2978073; hg19: chr8-38295542;