dbSNP rs4647904: FGFR1:c.2187-6C>T (chr8-38414029-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_023110.3(FGFR1):c.2187-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,613,888 control chromosomes in the GnomAD database, including 391 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 38 hom., cov: 33)

Exomes 𝑓: 0.019 ( 353 hom. )

Consequence

FGFR1
NM_023110.3 splice_region, intron

Scores

Splicing: ADA: 0.0005381

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.139

Publications

9 publications found

Variant links:

COSMIC-nc: COSV99050068

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

FGFR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 8-38414029-G-A is Benign according to our data. Variant chr8-38414029-G-A is described in ClinVar as Benign. ClinVar VariationId is 194786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0145 (2213/152250) while in subpopulation NFE AF = 0.0217 (1472/67990). AF 95% confidence interval is 0.0207. There are 38 homozygotes in GnomAd4. There are 1081 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 38 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FGFR1	NM_023110.3	MANE Select	c.2187-6C>T	splice_region intron	N/A	NP_075598.2	P11362-1
FGFR1	NM_001174067.2		c.2280-6C>T	splice_region intron	N/A	NP_001167538.1	P11362-21
FGFR1	NM_001354367.2		c.2181-6C>T	splice_region intron	N/A	NP_001341296.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FGFR1	ENST00000447712.7	TSL:1 MANE Select	c.2187-6C>T	splice_region intron	N/A	ENSP00000400162.2	P11362-1
FGFR1	ENST00000425967.8	TSL:1	c.2175-6C>T	splice_region intron	N/A	ENSP00000393312.4	A0A8I3B1S4
FGFR1	ENST00000397091.9	TSL:1	c.2181-6C>T	splice_region intron	N/A	ENSP00000380280.5	P11362-7

Frequencies

GnomAD3 genomes

AF:

0.0145

AC:

2213

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00319

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00850

Gnomad FIN

AF:

0.0413

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0216

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.0156

AC:

3895

AN:

249902

AF XY:

0.0158

show subpopulations

Gnomad AFR exome

AF:

0.00276

Gnomad AMR exome

AF:

0.00328

Gnomad ASJ exome

AF:

0.00984

Gnomad EAS exome

AF:

0.000110

Gnomad FIN exome

AF:

0.0401

Gnomad NFE exome

AF:

0.0209

Gnomad OTH exome

AF:

0.0140

GnomAD4 exome

AF:

0.0194

AC:

28407

AN:

1461638

Hom.:

353

Cov.:

AF XY:

0.0192

AC XY:

13982

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.00245

AC:

AN:

33480

American (AMR)

AF:

0.00367

AC:

164

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.0114

AC:

297

AN:

26130

East Asian (EAS)

AF:

0.000126

AC:

AN:

39698

South Asian (SAS)

AF:

0.0107

AC:

922

AN:

86228

European-Finnish (FIN)

AF:

0.0373

AC:

1989

AN:

53368

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0215

AC:

23906

AN:

1111882

Other (OTH)

AF:

0.0170

AC:

1025

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1715

3429

5144

6858

8573

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

874

1748

2622

3496

4370

<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:

0.0145

AC:

2213

AN:

152250

Hom.:

Cov.:

AF XY:

0.0145

AC XY:

1081

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00315

AC:

131

AN:

41546

American (AMR)

AF:

0.00418

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00871

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0413

AC:

439

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0217

AC:

1472

AN:

67990

Other (OTH)

AF:

0.00993

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

116

232

348

464

580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0182

Hom.:

Bravo

AF:

0.0116

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0190

EpiControl

AF:

0.0176

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (5)

Craniosynostosis syndrome (1)

Hypogonadotropic hypogonadism 2 with or without anosmia (1)

Osteoglophonic dysplasia (1)

Pfeiffer syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia (1)

Trigonocephaly 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.74

(source)

DANN

Uncertain

0.99

PhyloP100

0.14

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00054

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over