10-101774912-C-G

Position:

• chr10-101774912-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The ENST00000320185.7(FGF8):​c.157G>C​(p.Val53Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FGF8 ENST00000320185.7 missense, splice_region
• Scores: Splicing: ADA: 0.9966
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.99

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-101774912-C-G is Pathogenic according to our data. Variant chr10-101774912-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545459.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGF8	NM_033163.5	c.157G>C	p.Val53Leu	missense_variant, splice_region_variant	4/6	ENST00000320185.7	NP_149353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGF8	ENST00000320185.7	c.157G>C	p.Val53Leu	missense_variant, splice_region_variant	4/6	1	NM_033163.5	ENSP00000321797	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Holoprosencephaly sequence Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Muenke lab, National Institutes of Health

Apr 19, 2018

Consistent clinical presentation. One of multiple examples of alternative splicing eliminating the production of the most potent alternative splice forms. Predicted to be benign as an amino acid missense variation (BP3). This prediction was ignored based on splicing considerations of likely pathogenicity. ACMG criteria met: PVS1;PM2;PP3;PP6 (BP3 not considered). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.33	T
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.0	N;N
REVEL	Benign	0.23
Sift	Benign	0.52	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.93	P;P
Vest4		0.42
MutPred		0.28		Loss of sheet (P = 0.0037);.;
MVP		0.71
MPC		0.84
ClinPred		0.90	D
GERP RS		4.5
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.43		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554834889; hg19: chr10-103534669;