rs200890189

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_014845.6(FIG4):c.447-16G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0068 in 1,015,068 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 4 hom., cov: 26)

Exomes 𝑓: 0.0069 ( 29 hom. )

Consequence

FIG4
NM_014845.6 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.161

Publications

1 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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 6-109732621-G-T is Benign according to our data. Variant chr6-109732621-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR,Unknown,AD gene

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.447-16G>T		intron	N/A	NP_055660.1	Q92562

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FIG4	ENST00000230124.8	TSL:1 MANE Select	c.447-16G>T	intron	N/A	ENSP00000230124.4	Q92562
FIG4	ENST00000674884.1		c.447-16G>T	intron	N/A	ENSP00000502668.1	A0A6Q8PHH5
FIG4	ENST00000674744.1		c.447-16G>T	intron	N/A	ENSP00000501661.1	A0A6Q8PF62

Frequencies

GnomAD3 genomes

AF:

0.00599

AC:

882

AN:

147352

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00542

Gnomad ASJ

AF:

0.00756

Gnomad EAS

AF:

0.00118

Gnomad SAS

AF:

0.00170

Gnomad FIN

AF:

0.00417

Gnomad MID

AF:

0.00962

Gnomad NFE

AF:

0.00915

Gnomad OTH

AF:

0.00547

GnomAD2 exomes

AF:

0.00542

AC:

891

AN:

164298

AF XY:

0.00543

show subpopulations

Gnomad AFR exome

AF:

0.00180

Gnomad AMR exome

AF:

0.00408

Gnomad ASJ exome

AF:

0.00567

Gnomad EAS exome

AF:

0.000937

Gnomad FIN exome

AF:

0.00398

Gnomad NFE exome

AF:

0.00819

Gnomad OTH exome

AF:

0.00832

GnomAD4 exome

AF:

0.00693

AC:

6017

AN:

867668

Hom.:

Cov.:

AF XY:

0.00677

AC XY:

3050

AN XY:

450550

show subpopulations

African (AFR)

AF:

0.00256

AC:

AN:

19906

American (AMR)

AF:

0.00425

AC:

162

AN:

38076

Ashkenazi Jewish (ASJ)

AF:

0.00680

AC:

140

AN:

20600

East Asian (EAS)

AF:

0.000889

AC:

AN:

33756

South Asian (SAS)

AF:

0.00165

AC:

114

AN:

68934

European-Finnish (FIN)

AF:

0.00562

AC:

201

AN:

35760

Middle Eastern (MID)

AF:

0.00803

AC:

AN:

4236

European-Non Finnish (NFE)

AF:

0.00826

AC:

5013

AN:

606932

Other (OTH)

AF:

0.00689

AC:

272

AN:

39468

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

237

474

711

948

1185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<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:

0.00598

AC:

882

AN:

147400

Hom.:

Cov.:

AF XY:

0.00574

AC XY:

411

AN XY:

71602

show subpopulations

African (AFR)

AF:

0.00246

AC:

AN:

40318

American (AMR)

AF:

0.00541

AC:

AN:

14788

Ashkenazi Jewish (ASJ)

AF:

0.00756

AC:

AN:

3440

East Asian (EAS)

AF:

0.00119

AC:

AN:

5050

South Asian (SAS)

AF:

0.00171

AC:

AN:

4688

European-Finnish (FIN)

AF:

0.00417

AC:

AN:

9110

Middle Eastern (MID)

AF:

0.0104

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00915

AC:

611

AN:

66790

Other (OTH)

AF:

0.00543

AC:

AN:

2024

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

135

180

225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00394

Hom.:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease type 4 (1)

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

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.30

(source)

DANN

Benign

0.12

PhyloP100

-0.16

Mutation Taster

=100/0

polymorphism

(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