Genetic Variant FGF12:p.Arg52His (chr3-192335434-C-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_004113.6(FGF12):c.155G>A(p.Arg52His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

FGF12
NM_004113.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:19O:1

Conservation

PhyloP100: 7.57

Publications

33 publications found

Variant links:

Genes affected

FGF12 (HGNC:3668): (fibroblast growth factor 12) 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 growth factor lacks the N-terminal signal sequence present in most of the FGF family members, but it contains clusters of basic residues that have been demonstrated to act as a nuclear localization signal. When transfected into mammalian cells, this protein accumulated in the nucleus, but was not secreted. The specific function of this gene has not yet been determined. [provided by RefSeq, Dec 2019]

FGF12 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 47
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FGF12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.848

PP5

Variant 3-192335434-C-T is Pathogenic according to our data. Variant chr3-192335434-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 266034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004113.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FGF12	NM_004113.6	MANE Select	c.155G>A	p.Arg52His	missense	Exon 4 of 6	NP_004104.3
FGF12	NM_021032.5		c.341G>A	p.Arg114His	missense	Exon 3 of 5	NP_066360.1	P61328-1
FGF12	NM_001377293.1		c.83G>A	p.Arg28His	missense	Exon 3 of 5	NP_001364222.1	A0A804HIN2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FGF12	ENST00000445105.7	TSL:1 MANE Select	c.155G>A	p.Arg52His	missense	Exon 4 of 6	ENSP00000393686.1	P61328-2
FGF12	ENST00000454309.7	TSL:1	c.341G>A	p.Arg114His	missense	Exon 3 of 5	ENSP00000413496.2	P61328-1
FGF12	ENST00000450716.5	TSL:5	c.155G>A	p.Arg52His	missense	Exon 4 of 6	ENSP00000397635.1	P61328-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 47 (9)

not provided (9)

Seizure (1)

Early onset epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.075

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

0.0075

MutationAssessor

Uncertain

2.8

PhyloP100

7.6

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.55

Sift

Benign

0.075

Sift4G

Uncertain

0.019

Polyphen

0.87

Vest4

0.78

MutPred

0.76

Gain of catalytic residue at V111 (P = 0.2201)

MVP

0.92

MPC

2.0

ClinPred

0.98

GERP RS

5.5

Varity_R

0.61

gMVP

0.65

Mutation Taster

=0/100

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over