Genetic Variant FGF8:c.*124G>A (chr10-101770205-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033163.5(FGF8):c.*124G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000132 in 757,058 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)

Exomes 𝑓: 0.0000013 ( 0 hom. )

Consequence

FGF8
NM_033163.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.632

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

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>A	3_prime_UTR	Exon 6 of 6	NP_149353.1	P55075-4
FGF8	NM_033164.4		c.*124G>A	3_prime_UTR	Exon 6 of 6	NP_149354.1	P55075-1
FGF8	NM_006119.6		c.*124G>A	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>A	3_prime_UTR	Exon 6 of 6	ENSP00000321797.2	P55075-4
FGF8	ENST00000344255.8	TSL:1	c.*124G>A	3_prime_UTR	Exon 6 of 6	ENSP00000340039.3	P55075-1
FGF8	ENST00000469792.6	TSL:5	n.*823G>A	non_coding_transcript_exon	Exon 5 of 5	ENSP00000473299.1	R4GMQ3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000132

AC:

AN:

757058

Hom.:

Cov.:

AF XY:

0.00000264

AC XY:

AN XY:

378112

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17896

American (AMR)

AF:

0.00

AC:

AN:

17498

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15112

East Asian (EAS)

AF:

0.00

AC:

AN:

31324

South Asian (SAS)

AF:

0.0000222

AC:

AN:

45000

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2538

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

558714

Other (OTH)

AF:

0.00

AC:

AN:

35640

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

2.2

(source)

DANN

Benign

0.80

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over