rs121908287

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 13P and 2B. PS3PP3PP5_Very_StrongBP4BS2_Supporting

The NM_014845.6(FIG4):c.122T>C(p.Ile41Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00154 in 1,607,902 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000916118: Functional studies in proband fibroblasts, cultured cells, and yeast demonstrated that the p.Ile41Thr variant leads to low levels of protein due to impaired interaction with the scaffold protein, VAC14, which stabilizes FIG4 and impairs kinase activation (Chow et al. 2007" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I41V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 2 hom. )

Consequence

FIG4
NM_014845.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:35U:2B:2O:2

Conservation

PhyloP100: 5.73

Publications

61 publications found

Variant links:

Genes affected

FIG4 (HGNC:16873): (FIG4 phosphoinositide 5-phosphatase) The protein encoded by this gene belongs to the SAC domain-containing protein gene family. The SAC domain, approximately 400 amino acids in length and consisting of seven conserved motifs, has been shown to possess phosphoinositide phosphatase activity. The yeast homolog, Sac1p, is involved in the regulation of various phosphoinositides, and affects diverse cellular functions such as actin cytoskeleton organization, Golgi function, and maintenance of vacuole morphology. Membrane-bound phosphoinositides function as signaling molecules and play a key role in vesicle trafficking in eukaryotic cells. Mutations in this gene have been associated with Charcot-Marie-Tooth disease, type 4J. [provided by RefSeq, Jul 2008]

FIG4 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease
Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina, ClinGen
Charcot-Marie-Tooth disease type 4J
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
amyotrophic lateral sclerosis type 11
Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Yunis-Varon syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
bilateral parasagittal parieto-occipital polymicrogyria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FIG4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000916118: Functional studies in proband fibroblasts, cultured cells, and yeast demonstrated that the p.Ile41Thr variant leads to low levels of protein due to impaired interaction with the scaffold protein, VAC14, which stabilizes FIG4 and impairs kinase activation (Chow et al. 2007; Zhang et al. 2008; Ikonomov et al. 2010; Lenk et al. 2011).; SCV001430671: Functional studies in proband fibroblasts, cultured cells, and yeast demonstrate that the p.Ile41Thr substitution leads to low levels of FIG4 protein.; SCV001653109: "In vitro and in vivo functional studies both provide some evidence that this variant impacts protein function (first by de Leeuw 2008 PMID: 18261132) and animal models in mice have shown that this variant causes peripheral neuropathy (Gentil 2017: 28859335)."; SCV002548505: At least one publication reports experimental evidence evaluating an impact on protein function (Chow_2007). The most pronounced variant effect results in impaired activation of the Fab1/PIKfyve kinase resulting from decreased levels of phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2).; SCV000278978: Published functional studies demonstrate protein instability resulting in low levels of FIG4 protein (Lenk et al., 2011); SCV000603714: In support of this prediction, the p.Ile41Thr variant has been shown to impart instability to FIG4 protein (Ikonomov 2010, Lenk 2011). A FIG4 mouse model created using a null FIG4 allele and transgenic expression of the human p.Ile41Thr protein corroborates the conclusion that protein instability is likely the basis of the pathogenicity of the p.Ile41Thr variant (Lenk 2011, Winters 2011).; SCV000613294: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID 21655088); SCV005397435: Multiple functiol studies indicate that the variant protein has decreased function, stability, and ability to interact with scaffold proteins (PMID: 20630877, 21655088, 17572665).; SCV000546063: Experimental studies have shown that this missense change affects FIG4 function (PMID: 17572665, 20630877, 21655088).; SCV002061298: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product ( PMID: 17572665; 21655088) - PS3_moderate."

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Eigen, MutationAssessor, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 6-109715133-T-C is Pathogenic according to our data. Variant chr6-109715133-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.12936392). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD,Unknown geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014845.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FIG4	NM_014845.6	MANE Select	c.122T>C	p.Ile41Thr	missense	Exon 2 of 23	NP_055660.1	Q92562

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FIG4	ENST00000230124.8	TSL:1 MANE Select	c.122T>C	p.Ile41Thr	missense	Exon 2 of 23	ENSP00000230124.4	Q92562
FIG4	ENST00000675523.1		c.-110T>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 23	ENSP00000502384.1	A0A6Q8PGW5
FIG4	ENST00000674933.1		c.-110T>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 22	ENSP00000502376.1	A0A6Q8PGW0

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

177

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00204

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000981

AC:

246

AN:

250852

AF XY:

0.00100

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000753

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000468

Gnomad NFE exome

AF:

0.00187

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.00158

AC:

2293

AN:

1455608

Hom.:

Cov.:

AF XY:

0.00150

AC XY:

1085

AN XY:

724578

show subpopulations

African (AFR)

AF:

0.000210

AC:

AN:

33370

American (AMR)

AF:

0.000895

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39560

South Asian (SAS)

AF:

0.0000581

AC:

AN:

86114

European-Finnish (FIN)

AF:

0.000226

AC:

AN:

53050

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00194

AC:

2151

AN:

1106826

Other (OTH)

AF:

0.00128

AC:

AN:

60160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

183

275

366

458

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

240

320

400

<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

AF:

0.00116

AC:

177

AN:

152294

Hom.:

Cov.:

AF XY:

0.000886

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41554

American (AMR)

AF:

0.000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00204

AC:

139

AN:

68022

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00162

Hom.:

Bravo

AF:

0.00123

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000980

AC:

119

EpiCase

AF:

0.00169

EpiControl

AF:

0.00213

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (14)

Charcot-Marie-Tooth disease type 4J (9)

FIG4-related disorder (4)

Amyotrophic lateral sclerosis type 11 (3)

Yunis-Varon syndrome (3)

Amyotrophic lateral sclerosis (2)

Bilateral parasagittal parieto-occipital polymicrogyria (1)

Charcot-Marie-Tooth disease type 4 (1)

Inborn genetic diseases (1)

Yunis-Varon syndrome;C1970011:Charcot-Marie-Tooth disease type 4J (2)

Yunis-Varon syndrome;C1970011:Charcot-Marie-Tooth disease type 4J;C2675491:Amyotrophic lateral sclerosis type 11;C4013648:Bilateral parasagittal parieto-occipital polymicrogyria (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.13

MetaSVM

Uncertain

0.51

MutationAssessor

Pathogenic

3.7

PhyloP100

5.7

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.98

MVP

0.81

MPC

1.2

ClinPred

0.28

GERP RS

5.7

Varity_R

0.71

gMVP

0.85

Mutation Taster

=58/42

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over