8-38428088-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_023110.3(FGFR1):c.454G>T(p.Ala152Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A152P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

FGFR1
NM_023110.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.96

Publications

1 publications found

Variant links:

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

FGFR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.33993185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3 link	c.454G>T	p.Ala152Ser	missense_variant	Exon 5 of 18	ENST00000447712.7	NP_075598.2	P11362-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FGFR1	ENST00000447712.7 link	c.454G>T	p.Ala152Ser	missense_variant	Exon 5 of 18	1	NM_023110.3	ENSP00000400162.2	P11362-1
FGFR1	ENST00000397091.9 link	c.448G>T	p.Ala150Ser	missense_variant	Exon 5 of 18	1		ENSP00000380280.5	P11362-7
FGFR1	ENST00000397108.8 link	c.448G>T	p.Ala150Ser	missense_variant	Exon 6 of 19	1		ENSP00000380297.4	P11362-7
FGFR1	ENST00000397113.6 link	c.448G>T	p.Ala150Ser	missense_variant	Exon 5 of 18	2		ENSP00000380302.2	P11362-7
FGFR1	ENST00000356207.9 link	c.187G>T	p.Ala63Ser	missense_variant	Exon 4 of 17	1		ENSP00000348537.5	P11362-3
FGFR1	ENST00000397103.5 link	c.181G>T	p.Ala61Ser	missense_variant	Exon 3 of 16	5		ENSP00000380292.1	E7EU09
FGFR1	ENST00000326324.10 link	c.181G>T	p.Ala61Ser	missense_variant	Exon 4 of 17	1		ENSP00000327229.6	P11362-14
FGFR1	ENST00000487647.5 link	n.*145G>T		non_coding_transcript_exon_variant	Exon 4 of 12	1		ENSP00000435254.1	E9PKX3
FGFR1	ENST00000487647.5 link	n.*145G>T		3_prime_UTR_variant	Exon 4 of 12	1		ENSP00000435254.1	E9PKX3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

249412

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

.;.;D;T;.;.;.;.;.;.;T;.;T;.;T;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

D;.;D;D;D;D;.;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.068

MetaRNN

Benign

0.34

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

1.9

.;.;L;.;.;L;.;.;.;.;.;.;.;.;.;.

PhyloP100

4.0

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.7

N;N;N;.;N;N;N;N;N;N;N;N;N;N;N;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.0060

D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Benign

0.20

T;T;T;D;T;T;T;T;T;T;T;T;.;.;D;.

Polyphen

0.92

P;P;P;B;.;P;P;P;B;P;.;P;.;.;.;.

Vest4

0.33

MutPred

0.35

.;.;Gain of phosphorylation at A152 (P = 0.0311);.;.;Gain of phosphorylation at A152 (P = 0.0311);.;.;.;.;.;.;Gain of phosphorylation at A152 (P = 0.0311);.;.;.;

MVP

0.73

MPC

0.053

ClinPred

0.24

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.62

gMVP

0.67

Mutation Taster

=33/67

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over