Genetic Variant NM_005247.4:c.196G>A (chr11-69818738-C-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_005247.4(FGF3):c.196G>A(p.Gly66Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000373 in 1,341,960 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. G66C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Consequence

FGF3
NM_005247.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.25

Publications

8 publications found

Variant links:

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]

FGF3 Gene-Disease associations (from GenCC):

deafness with labyrinthine aplasia, microtia, and microdontia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

FGF3 links:

LOC107984368 (HGNC:):

LOC107984368 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a chain Fibroblast growth factor 3 (size 221) in uniprot entity FGF3_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) 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 chr11-69818738-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 13840.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF3	NM_005247.4 link	c.196G>A	p.Gly66Ser	missense_variant	Exon 1 of 3	ENST00000334134.4	NP_005238.1	P11487A0A7U3JVY0
LOC107984368	XR_001748071.2 link	n.31C>T		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF3	ENST00000334134.4 link	c.196G>A	p.Gly66Ser	missense_variant	Exon 1 of 3	1	NM_005247.4	ENSP00000334122.2		P11487
ENSG00000300527	ENST00000772585.1 link	n.-233C>T		upstream_gene_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000373

AC:

AN:

1341960

Hom.:

Cov.:

AF XY:

0.00000151

AC XY:

AN XY:

662230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27310

American (AMR)

AF:

0.00

AC:

AN:

30694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23702

East Asian (EAS)

AF:

0.00

AC:

AN:

30622

South Asian (SAS)

AF:

0.00

AC:

AN:

75086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33940

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4388

European-Non Finnish (NFE)

AF:

0.00000471

AC:

AN:

1060476

Other (OTH)

AF:

0.00

AC:

AN:

55742

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000896

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.090

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.25

MutationAssessor

Pathogenic

3.2

PhyloP100

4.3

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.74

Sift

Uncertain

0.028

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.51

MutPred

0.92

Gain of phosphorylation at G66 (P = 0.0469);

MVP

0.91

MPC

0.96

ClinPred

1.0

GERP RS

2.6

Varity_R

0.47

gMVP

0.82

Mutation Taster

=11/89

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over