dbSNP rs3218239: FGF8:c.*124G>C (chr10-101770205-C-G) – 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_033163.5(FGF8):c.*124G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 908,996 control chromosomes in the GnomAD database, including 242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 24 hom., cov: 33)

Exomes 𝑓: 0.020 ( 218 hom. )

Consequence

FGF8
NM_033163.5 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.632

Publications

2 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:

ENSG00000308881 (HGNC:):

ENSG00000308881 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=-0.77).

BP6

Variant 10-101770205-C-G is Benign according to our data. Variant chr10-101770205-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1219940.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 = 0.0153 (2327/152138) while in subpopulation NFE AF = 0.0255 (1732/67966). AF 95% confidence interval is 0.0245. There are 24 homozygotes in GnomAd4. There are 1054 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AD,AR gene

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	Effect	Exon Rank	Protein	UniProt
FGF8	NM_033163.5	MANE Select	c.*124G>C	3_prime_UTR	Exon 6 of 6	NP_149353.1	P55075-4
FGF8	NM_033164.4		c.*124G>C	3_prime_UTR	Exon 6 of 6	NP_149354.1	P55075-1
FGF8	NM_006119.6		c.*124G>C	3_prime_UTR	Exon 5 of 5	NP_006110.1	P55075-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FGF8	ENST00000320185.7	TSL:1 MANE Select	c.*124G>C	3_prime_UTR	Exon 6 of 6	ENSP00000321797.2	P55075-4
FGF8	ENST00000344255.8	TSL:1	c.*124G>C	3_prime_UTR	Exon 6 of 6	ENSP00000340039.3	P55075-1
FGF8	ENST00000469792.6	TSL:5	n.*823G>C	non_coding_transcript_exon	Exon 5 of 5	ENSP00000473299.1	R4GMQ3

Frequencies

GnomAD3 genomes

AF:

0.0153

AC:

2328

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00493

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.00864

Gnomad ASJ

AF:

0.0132

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0150

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0255

Gnomad OTH

AF:

0.0110

GnomAD4 exome

AF:

0.0198

AC:

15015

AN:

756858

Hom.:

218

Cov.:

AF XY:

0.0192

AC XY:

7272

AN XY:

378006

show subpopulations

African (AFR)

AF:

0.00358

AC:

AN:

17894

American (AMR)

AF:

0.00720

AC:

126

AN:

17498

Ashkenazi Jewish (ASJ)

AF:

0.0119

AC:

180

AN:

15110

East Asian (EAS)

AF:

0.0000319

AC:

AN:

31324

South Asian (SAS)

AF:

0.00260

AC:

117

AN:

45000

European-Finnish (FIN)

AF:

0.0199

AC:

663

AN:

33332

Middle Eastern (MID)

AF:

0.00473

AC:

AN:

2538

European-Non Finnish (NFE)

AF:

0.0238

AC:

13282

AN:

558524

Other (OTH)

AF:

0.0160

AC:

570

AN:

35638

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

704

1408

2111

2815

3519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

384

768

1152

1536

1920

<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:

0.0153

AC:

2327

AN:

152138

Hom.:

Cov.:

AF XY:

0.0142

AC XY:

1054

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.00491

AC:

204

AN:

41506

American (AMR)

AF:

0.00863

AC:

132

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0132

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00270

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0150

AC:

159

AN:

10584

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0255

AC:

1732

AN:

67966

Other (OTH)

AF:

0.0109

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

104

208

311

415

519

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:

0.0193

Hom.:

Bravo

AF:

0.0153

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.8

(source)

DANN

Benign

0.73

PhyloP100

-0.63

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over