11-69816361-G-C

Variant names:

• chr11-69816361-G-C
• NM_005247.4:c.283C>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_005247.4(FGF3):​c.283C>G​(p.Arg95Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R95W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FGF3 NM_005247.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.57

Genes affected

FGF3 (HGNC:3681): (fibroblast growth factor 3) 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 gene was identified by its similarity with mouse fgf3/int-2, a proto-oncogene activated in virally induced mammary tumors in the mouse. Frequent amplification of this gene has been found in human tumors, which may be important for neoplastic transformation and tumor progression. Studies of the similar genes in mouse and chicken suggested the role in inner ear formation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a chain Fibroblast growth factor 3 (size 221) in uniprot entity FGF3_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_005247.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-69816361-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF3	NM_005247.4	c.283C>G	p.Arg95Gly	missense_variant	Exon 2 of 3	ENST00000334134.4	NP_005238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF3	ENST00000334134.4	c.283C>G	p.Arg95Gly	missense_variant	Exon 2 of 3	1	NM_005247.4	ENSP00000334122.2
FGF3	ENST00000646078.1	n.130C>G		non_coding_transcript_exon_variant	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461788 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727212

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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.66
Sift	Benign	0.18	T
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.90
MutPred		0.77		Loss of methylation at R95 (P = 0.0186);
MVP		0.83
MPC		1.1
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.87
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-69631129;