chr8-38413783-G-A

Variant names:

• chr8-38413783-G-A
• rs56234888
• NM_023110.3:c.2314C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_023110.3(FGFR1):​c.2314C>T​(p.Pro772Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00224 in 1,614,080 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P772T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (45 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (38 hom.)
• Consequence: FGFR1 NM_023110.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 4.90
• Publications: 24 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: G2P, Ambry Genetics, Orphanet, ClinGen
• hypogonadotropic hypogonadism 2 with or without anosmia

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• osteoglophonic dysplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp, Orphanet
• Pfeiffer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Pfeiffer syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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 -19 ACMG points.

• PP2: Missense variant in the FGFR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 93 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 2.4852 (below the threshold of 3.09). Trascript score misZ: 4.2642 (above the threshold of 3.09). GenCC associations: The gene is linked to Hartsfield-Bixler-Demyer syndrome, Pfeiffer syndrome type 1, encephalocraniocutaneous lipomatosis, hypogonadotropic hypogonadism 2 with or without anosmia, osteoglophonic dysplasia, isolated trigonocephaly, septooptic dysplasia, Pfeiffer syndrome, tooth agenesis, hypogonadotropic hypogonadism, Kallmann syndrome, holoprosencephaly, Jackson-Weiss syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.00591293).
• BP6: Variant 8-38413783-G-A is Benign according to our data. Variant chr8-38413783-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0121 (1837/152232) while in subpopulation AFR AF = 0.0421 (1750/41542). AF 95% confidence interval is 0.0405. There are 45 homozygotes in GnomAd4. There are 846 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR1	NM_023110.3	MANE Select	c.2314C>T	p.Pro772Ser	missense	Exon 18 of 18	NP_075598.2	P11362-1
	FGFR1	NM_001174067.2		c.2407C>T	p.Pro803Ser	missense	Exon 19 of 19	NP_001167538.1	P11362-21
	FGFR1	NM_001174063.2		c.2308C>T	p.Pro770Ser	missense	Exon 18 of 18	NP_001167534.1	A0A0S2Z3Q6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR1	ENST00000447712.7	TSL:1 MANE Select	c.2314C>T	p.Pro772Ser	missense	Exon 18 of 18	ENSP00000400162.2	P11362-1
	FGFR1	ENST00000397091.9	TSL:1	c.2308C>T	p.Pro770Ser	missense	Exon 18 of 18	ENSP00000380280.5	P11362-7
	FGFR1	ENST00000397108.8	TSL:1	c.2308C>T	p.Pro770Ser	missense	Exon 19 of 19	ENSP00000380297.4	P11362-7

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1835 AN: 152114 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.0422

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00312 AC: 777 AN: 249124 AF XY: 0.00226

Gnomad AFR exome AF: 0.0453

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000992

GnomAD4 exome AF: 0.00122 AC: 1780 AN: 1461848 Hom.: 38 Cov.: 32 AF XY: 0.00101 AC XY: 737 AN XY: 727226

African (AFR) AF: 0.0433 AC: 1450 AN: 33480

American (AMR) AF: 0.00186 AC: 83 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5766

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1112000

Other (OTH) AF: 0.00298 AC: 180 AN: 60392

GnomAD4 genome AF: 0.0121 AC: 1837 AN: 152232 Hom.: 45 Cov.: 32 AF XY: 0.0114 AC XY: 846 AN XY: 74420

African (AFR) AF: 0.0421 AC: 1750 AN: 41542

American (AMR) AF: 0.00360 AC: 55 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67978

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00409 Hom.: 23

Bravo AF: 0.0141

ESP6500AA AF: 0.0417 AC: 171

ESP6500EA AF: 0.000238 AC: 2

ExAC AF: 0.00383 AC: 464

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Hypogonadotropic hypogonadism 2 with or without anosmia (2)
-	-	1	Craniosynostosis syndrome (1)
-	-	1	Osteoglophonic dysplasia (1)
-	-	1	Pfeiffer syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia (1)
-	-	1	Trigonocephaly 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.42
Sift	Benign	0.083	T
Sift4G	Benign	0.094	T
Polyphen		0.42	B
Vest4		0.14
MVP		0.61
MPC		1.1
ClinPred		0.041	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.55
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs56234888; hg19: chr8-38271301; COSMIC: COSV58339882; COSMIC: COSV58339882;