Genetic Variant ENSG00000305763:n.66+2325T>C (chr8-38468886-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000812829.1(ENSG00000305763):n.66+2325T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 226,984 control chromosomes in the GnomAD database, including 15,618 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 0.36 ( 10142 hom., cov: 34)

Exomes 𝑓: 0.38 ( 5476 hom. )

Consequence

ENSG00000305763
ENST00000812829.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0370

Publications

9 publications found

Variant links:

Genes affected

ENSG00000305763 (HGNC:):

ENSG00000305763 links:

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein
ENSG00000305763	ENST00000812829.1 link	n.66+2325T>C	intron_variant	Intron 1 of 3
FGFR1	ENST00000397091.9 link	c.-994A>G	upstream_gene_variant		1	ENSP00000380280.5
FGFR1	ENST00000703405.1 link	c.-994A>G	upstream_gene_variant			ENSP00000515291.1
FGFR1	ENST00000619564.3 link	n.-994A>G	upstream_gene_variant		5	ENSP00000484553.1

Frequencies

GnomAD3 genomes

AF:

0.357

AC:

54284

AN:

152020

Hom.:

10133

Cov.:

show subpopulations

Gnomad AFR

AF:

0.259

Gnomad AMI

AF:

0.435

Gnomad AMR

AF:

0.284

Gnomad ASJ

AF:

0.345

Gnomad EAS

AF:

0.352

Gnomad SAS

AF:

0.515

Gnomad FIN

AF:

0.409

Gnomad MID

AF:

0.389

Gnomad NFE

AF:

0.414

Gnomad OTH

AF:

0.335

GnomAD4 exome

AF:

0.379

AC:

28340

AN:

74844

Hom.:

5476

AF XY:

0.384

AC XY:

13289

AN XY:

34648

show subpopulations

African (AFR)

AF:

0.272

AC:

952

AN:

3502

American (AMR)

AF:

0.265

AC:

597

AN:

2252

Ashkenazi Jewish (ASJ)

AF:

0.357

AC:

1687

AN:

4732

East Asian (EAS)

AF:

0.309

AC:

3379

AN:

10920

South Asian (SAS)

AF:

0.558

AC:

366

AN:

656

European-Finnish (FIN)

AF:

0.485

AC:

AN:

Middle Eastern (MID)

AF:

0.456

AC:

206

AN:

452

European-Non Finnish (NFE)

AF:

0.408

AC:

18823

AN:

46094

Other (OTH)

AF:

0.372

AC:

2298

AN:

6170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

903

1806

2709

3612

4515

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<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

AF:

0.357

AC:

54300

AN:

152140

Hom.:

10142

Cov.:

AF XY:

0.359

AC XY:

26715

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.259

AC:

10745

AN:

41526

American (AMR)

AF:

0.283

AC:

4333

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.345

AC:

1198

AN:

3472

East Asian (EAS)

AF:

0.351

AC:

1814

AN:

5164

South Asian (SAS)

AF:

0.516

AC:

2489

AN:

4826

European-Finnish (FIN)

AF:

0.409

AC:

4329

AN:

10580

Middle Eastern (MID)

AF:

0.388

AC:

114

AN:

294

European-Non Finnish (NFE)

AF:

0.414

AC:

28170

AN:

67974

Other (OTH)

AF:

0.338

AC:

712

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1883

3766

5648

7531

9414

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

554

1108

1662

2216

2770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.249

Hom.:

652

Bravo

AF:

0.337

Asia WGS

AF:

0.431

AC:

1499

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

8.2

(source)

DANN

Benign

0.59

PhyloP100

-0.037

PromoterAI

0.0069

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over