rs200776757

Variant names:

• chr8-38418290-C-A
• rs200776757
• NM_023110.3:c.1368G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-38418290-C-A
• chr8-38418290-C-G
• chr8-38418290-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2 BP6 BS1

The NM_023110.3(FGFR1):​c.1368G>T​(p.Met456Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000561 in 1,614,218 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (0 hom.)
• Consequence: FGFR1 NM_023110.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:10
• Conservation: PhyloP100: 7.90
• Publications: 23 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: Likely_benign. The variant received -4 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 hypogonadotropic hypogonadism 2 with or without anosmia, Hartsfield-Bixler-Demyer syndrome, Pfeiffer syndrome, osteoglophonic dysplasia, Pfeiffer syndrome type 1, encephalocraniocutaneous lipomatosis, Jackson-Weiss syndrome, isolated trigonocephaly, holoprosencephaly, tooth agenesis, Kallmann syndrome, hypogonadotropic hypogonadism, septooptic dysplasia.
• BP6: Variant 8-38418290-C-A is Benign according to our data. Variant chr8-38418290-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 362896.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000427 (65/152346) while in subpopulation NFE AF = 0.000779 (53/68032). AF 95% confidence interval is 0.000612. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1368G>T	p.Met456Ile	missense	Exon 10 of 18	NP_075598.2	P11362-1
	FGFR1	NM_001174067.2		c.1461G>T	p.Met487Ile	missense	Exon 11 of 19	NP_001167538.1	P11362-21
	FGFR1	NM_001354367.2		c.1362G>T	p.Met454Ile	missense	Exon 10 of 18	NP_001341296.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR1	ENST00000447712.7	TSL:1 MANE Select	c.1368G>T	p.Met456Ile	missense	Exon 10 of 18	ENSP00000400162.2	P11362-1
	FGFR1	ENST00000425967.8	TSL:1	c.1356G>T	p.Met452Ile	missense	Exon 10 of 18	ENSP00000393312.4	A0A8I3B1S4
	FGFR1	ENST00000397091.9	TSL:1	c.1362G>T	p.Met454Ile	missense	Exon 10 of 18	ENSP00000380280.5	P11362-7

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000421 AC: 105 AN: 249554 AF XY: 0.000421

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000821

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000575 AC: 840 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.000568 AC XY: 413 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53400

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000716 AC: 796 AN: 1112010

Other (OTH) AF: 0.000315 AC: 19 AN: 60396

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74502

African (AFR) AF: 0.0000962 AC: 4 AN: 41586

American (AMR) AF: 0.000392 AC: 6 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000759 Hom.: 0

Bravo AF: 0.000563

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000598 AC: 5

ExAC AF: 0.000388 AC: 47

EpiCase AF: 0.000545

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	1	1	Hypogonadotropic hypogonadism 2 with or without anosmia (2)
-	-	1	Craniosynostosis syndrome (1)
-	-	1	Craniosynostosis, nonspecific (1)
-	-	1	Osteoglophonic dysplasia (1)
-	1	-	Pfeiffer syndrome;C0406612:Encephalocraniocutaneous lipomatosis;C0432122:Trigonocephaly 1;C0432283:Osteoglophonic dysplasia;C0795998:Jackson-Weiss syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia;C1845146:Hartsfield-Bixler-Demyer syndrome (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	Uncertain	0.43
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.017	D
Sift4G	Benign	0.23	T
Polyphen		0.077	B
Vest4		0.90
MutPred		0.29		Loss of loop (P = 0.1258)
MVP		0.79
MPC		0.22
ClinPred		0.090	T
GERP RS		5.4
Varity_R		0.58
gMVP		0.56
Mutation Taster		=0/100	disease causing

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: rs200776757; hg19: chr8-38275808; COSMIC: COSV58341155;