dbSNP rs137852660: FGF8:p.Pro26Leu (chr10-101775209-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS1

The NM_033163.5(FGF8):c.77C>T(p.Pro26Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,539,758 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P26R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00084 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 0 hom. )

Consequence

FGF8
NM_033163.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:2O:1

Conservation

PhyloP100: 0.854

Publications

21 publications found

Variant links:

Genes affected

FGF8 (HGNC:3686): (fibroblast growth factor 8) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This protein is known to be a factor that supports androgen and anchorage independent growth of mammary tumor cells. Overexpression of this gene has been shown to increase tumor growth and angiogensis. The adult expression of this gene is restricted to testes and ovaries. Temporal and spatial pattern of this gene expression suggests its function as an embryonic epithelial factor. Studies of the mouse and chick homologs revealed roles in midbrain and limb development, organogenesis, embryo gastrulation and left-right axis determination. The alternative splicing of this gene results in four transcript variants. [provided by RefSeq, Jul 2008]

FGF8 Gene-Disease associations (from GenCC):

hypogonadotropic hypogonadism 6 with or without anosmia
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
congenital heart disease
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
hypogonadotropic hypogonadism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Kallmann syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
holoprosencephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FGF8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.5674 (below the threshold of 3.09). Trascript score misZ: 1.0113 (below the threshold of 3.09). GenCC associations: The gene is linked to hypogonadotropic hypogonadism, holoprosencephaly, hypogonadotropic hypogonadism 6 with or without anosmia, Kallmann syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.06352016).

BP6

Variant 10-101775209-G-A is Benign according to our data. Variant chr10-101775209-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 9122.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000843 (128/151926) while in subpopulation SAS AF = 0.00145 (7/4830). AF 95% confidence interval is 0.00115. There are 1 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033163.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FGF8	NM_033163.5	MANE Select	c.77C>T	p.Pro26Leu	missense	Exon 3 of 6	NP_149353.1	P55075-4
FGF8	NM_033164.4		c.77C>T	p.Pro26Leu	missense	Exon 3 of 6	NP_149354.1	P55075-1
FGF8	NM_006119.6		c.70-297C>T		intron	N/A	NP_006110.1	P55075-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FGF8	ENST00000320185.7	TSL:1 MANE Select	c.77C>T	p.Pro26Leu	missense	Exon 3 of 6	ENSP00000321797.2	P55075-4
FGF8	ENST00000344255.8	TSL:1	c.77C>T	p.Pro26Leu	missense	Exon 3 of 6	ENSP00000340039.3	P55075-1
FGF8	ENST00000347978.2	TSL:1	c.70-297C>T		intron	N/A	ENSP00000321945.2	P55075-3

Frequencies

GnomAD3 genomes

AF:

0.000843

AC:

128

AN:

151808

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.00115

AC:

167

AN:

145328

AF XY:

0.00111

show subpopulations

Gnomad AFR exome

AF:

0.000150

Gnomad AMR exome

AF:

0.000408

Gnomad ASJ exome

AF:

0.00523

Gnomad EAS exome

AF:

0.0000934

Gnomad FIN exome

AF:

0.00143

Gnomad NFE exome

AF:

0.00119

Gnomad OTH exome

AF:

0.000718

GnomAD4 exome

AF:

0.00107

AC:

1484

AN:

1387832

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

758

AN XY:

684482

show subpopulations

African (AFR)

AF:

0.000127

AC:

AN:

31502

American (AMR)

AF:

0.000532

AC:

AN:

35682

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

145

AN:

25154

East Asian (EAS)

AF:

0.00

AC:

AN:

35712

South Asian (SAS)

AF:

0.00121

AC:

AN:

79152

European-Finnish (FIN)

AF:

0.000890

AC:

AN:

47206

Middle Eastern (MID)

AF:

0.000458

AC:

AN:

4366

European-Non Finnish (NFE)

AF:

0.00102

AC:

1098

AN:

1071410

Other (OTH)

AF:

0.00135

AC:

AN:

57648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

171

256

342

427

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<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:

0.000843

AC:

128

AN:

151926

Hom.:

Cov.:

AF XY:

0.000713

AC XY:

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41558

American (AMR)

AF:

0.000196

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00145

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00137

AC:

AN:

67654

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00149

Hom.:

Bravo

AF:

0.000706

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000689

AC:

ExAC

AF:

0.000584

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypogonadotropic hypogonadism 6 with or without anosmia (4)

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Uncertain

0.51

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.67

M_CAP

Benign

0.050

MetaRNN

Benign

0.064

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.7

PhyloP100

0.85

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.45

REVEL

Uncertain

0.49

Sift

Benign

0.40

Sift4G

Uncertain

0.030

Polyphen

0.0010

Vest4

0.48

MVP

0.94

MPC

0.85

ClinPred

0.012

GERP RS

-0.41

Varity_R

0.047

gMVP

0.46

Mutation Taster

=11/89

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.070

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