10-101770373-T-C

Variant names:

• chr10-101770373-T-C
• rs1394398993
• NM_033163.5:c.691A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_033163.5(FGF8):​c.691A>G​(p.Ser231Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000552 in 1,450,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: FGF8 NM_033163.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.49

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18361804).
• BS2: High AC in GnomAdExome4 at 8 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF8	NM_033163.5	c.691A>G	p.Ser231Gly	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.691A>G	p.Ser231Gly	missense_variant	Exon 6 of 6	1	NM_033163.5	ENSP00000321797.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000552 AC: 8 AN: 1450192 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 720470

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: 0.00000722

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.691A>G (p.S231G) alteration is located in exon 6 (coding exon 6) of the FGF8 gene. This alteration results from a A to G substitution at nucleotide position 691, causing the serine (S) at amino acid position 231 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	.;D;.;.;.
Eigen	Benign	-0.073
Eigen_PC	Benign	-0.00089
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.2	.;L;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.3	.;N;N;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.011	.;D;D;D;D
Sift4G	Benign	0.15	T;T;D;T;T
Polyphen		0.74, 0.82, 0.68	.;P;P;P;P
Vest4		0.14
MutPred		0.17		.;Loss of phosphorylation at S220 (P = 0.0388);.;.;.;
MVP		0.61
MPC		1.2
ClinPred		0.71	D
GERP RS		2.5
Varity_R		0.20
gMVP		0.40

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: rs1394398993; hg19: chr10-103530130;