8-38424565-C-T

Position:

chr8-38424565-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP5_Moderate

The NM_023110.3(FGFR1):c.880G>A(p.Glu294Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,242 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FGFR1
NM_023110.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.17

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 links:

FGFR1 (HGNC:):

FGFR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a domain Ig-like C2-type 3 (size 102) in uniprot entity FGFR1_HUMAN there are 42 pathogenic changes around while only 1 benign (98%) in NM_023110.3

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FGFR1. . Gene score misZ 2.4852 (greater than the threshold 3.09). Trascript score misZ 4.2642 (greater than threshold 3.09). GenCC has associacion of gene with hypogonadotropic hypogonadism 2 with or without anosmia, encephalocraniocutaneous lipomatosis, hypogonadotropic hypogonadism, tooth agenesis, isolated trigonocephaly, Pfeiffer syndrome type 1, Jackson-Weiss syndrome, Pfeiffer syndrome, Kallmann syndrome, septooptic dysplasia, hypogonadotropic hypogonadism 7 with or without anosmia, holoprosencephaly, osteoglophonic dwarfism, Hartsfield-Bixler-Demyer syndrome.

PP5

Variant 8-38424565-C-T is Pathogenic according to our data. Variant chr8-38424565-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 517665.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR1	NM_023110.3 linkuse as main transcript	c.880G>A	p.Glu294Lys	missense_variant	7/18	ENST00000447712.7	NP_075598.2	P11362-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FGFR1	ENST00000447712.7 linkuse as main transcript	c.880G>A	p.Glu294Lys	missense_variant	7/18	1	NM_023110.3	ENSP00000400162.2	P11362-1
FGFR1	ENST00000397091.9 linkuse as main transcript	c.874G>A	p.Glu292Lys	missense_variant	7/18	1		ENSP00000380280.5	P11362-7
FGFR1	ENST00000397108.8 linkuse as main transcript	c.874G>A	p.Glu292Lys	missense_variant	8/19	1		ENSP00000380297.4	P11362-7
FGFR1	ENST00000397113.6 linkuse as main transcript	c.874G>A	p.Glu292Lys	missense_variant	7/18	2		ENSP00000380302.2	P11362-7
FGFR1	ENST00000356207.9 linkuse as main transcript	c.613G>A	p.Glu205Lys	missense_variant	6/17	1		ENSP00000348537.5	P11362-3
FGFR1	ENST00000397103.5 linkuse as main transcript	c.607G>A	p.Glu203Lys	missense_variant	5/16	5		ENSP00000380292.1	E7EU09
FGFR1	ENST00000326324.10 linkuse as main transcript	c.607G>A	p.Glu203Lys	missense_variant	6/17	1		ENSP00000327229.6	P11362-14
FGFR1	ENST00000487647.5 linkuse as main transcript	n.*571G>A		non_coding_transcript_exon_variant	6/12	1		ENSP00000435254.1	E9PKX3
FGFR1	ENST00000487647.5 linkuse as main transcript	n.*571G>A		3_prime_UTR_variant	6/12	1		ENSP00000435254.1	E9PKX3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249612

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135410

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000224

Hom.:

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Holoprosencephaly sequence

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Muenke lab, National Institutes of Health

Mar 08, 2018

Co-inherited FGF8 loss-of-function in two affected sibs. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

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

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

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

M_CAP

Uncertain

0.28

MetaRNN

Uncertain

0.73

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.72

MutationAssessor

Benign

1.0

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

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.7

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

REVEL

Uncertain

0.60

Sift

Uncertain

0.0050

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

Sift4G

Benign

0.27

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

Polyphen

0.89

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

Vest4

0.50

MutPred

0.63

.;.;Gain of methylation at E294 (P = 0.0077);.;.;Gain of methylation at E294 (P = 0.0077);.;.;.;.;.;.;.;Gain of methylation at E294 (P = 0.0077);

MVP

0.98

MPC

1.7

ClinPred

0.85

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.27

Position offset: -2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over