rs778082287

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

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

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]

LOC105378457 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF8	NM_033163.5	c.497A>G	p.Asn166Ser	missense_variant	Exon 6 of 6	ENST00000320185.7	NP_149353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF8	ENST00000320185.7	c.497A>G	p.Asn166Ser	missense_variant	Exon 6 of 6	1	NM_033163.5	ENSP00000321797.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250692 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135596

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Holoprosencephaly sequence Uncertain:1

Apr 18, 2018

Muenke lab, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Statistically different in zebrafish functional studies compared to the normal FGF8 isoform. However, experimental variability was detected between repeated independent studies. Experimental and bioinformatic predictions suggest a weak hypomorph. ACMG: PS3;PP3 (variable hypomorph; site affected by glycosylation based on this variant as well as synthetic codon variants tested for glycosylation changes reflected by altered electrophoretic mobility in Western blots). Stronger loss of activity seen with purely synthetic codon variants. -

Computational scores

Source: dbNSFP v4.3

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;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.71	D;D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.0	.;M;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.0	.;D;D;D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.027	.;D;T;D;D
Sift4G	Uncertain	0.030	D;D;D;D;D
Polyphen		1.0, 0.029, 0.15	.;D;B;B;B
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs778082287; hg19: chr10-103530324;