rs778082287

Variant names:

• chr10-101770567-T-C
• rs778082287
• NM_033163.5:c.497A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_033163.5(FGF8):​c.497A>G​(p.Asn166Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FGF8 NM_033163.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.87
• Publications: 0 publications found

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
• 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

ENSG00000308881 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF8	NM_033163.5	MANE Select	c.497A>G	p.Asn166Ser	missense	Exon 6 of 6	NP_149353.1
	FGF8	NM_033164.4		c.464A>G	p.Asn155Ser	missense	Exon 6 of 6	NP_149354.1
	FGF8	NM_006119.6		c.410A>G	p.Asn137Ser	missense	Exon 5 of 5	NP_006110.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF8	ENST00000320185.7	TSL:1 MANE Select	c.497A>G	p.Asn166Ser	missense	Exon 6 of 6	ENSP00000321797.2
	FGF8	ENST00000344255.8	TSL:1	c.464A>G	p.Asn155Ser	missense	Exon 6 of 6	ENSP00000340039.3
	FGF8	ENST00000347978.2	TSL:1	c.410A>G	p.Asn137Ser	missense	Exon 5 of 5	ENSP00000321945.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250692 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460870 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726784

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111948

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Holoprosencephaly sequence (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
Eigen	Benign	0.075
Eigen_PC	Benign	0.089
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.68		Loss of stability (P = 0.099)
MVP		0.73
MPC		0.87
ClinPred		0.53	D
GERP RS		3.7
Varity_R		0.89
gMVP		0.59
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs778082287; hg19: chr10-103530324;