rs56378532

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_014845.6(FIG4):c.67-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0527 in 1,501,586 control chromosomes in the GnomAD database, including 2,420 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.043 ( 175 hom., cov: 32)

Exomes 𝑓: 0.054 ( 2245 hom. )

Consequence

FIG4
NM_014845.6 splice_region, intron

Scores

Splicing: ADA: 0.0005026

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.413

Publications

9 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: ClinGen, Illumina
Charcot-Marie-Tooth disease type 4J
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Laboratory for Molecular Medicine
Yunis-Varon syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
amyotrophic lateral sclerosis type 11
Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 6-109715071-T-C is Benign according to our data. Variant chr6-109715071-T-C is described in ClinVar as Benign. ClinVar VariationId is 137374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FIG4	NM_014845.6 link	c.67-7T>C		splice_region_variant, intron_variant	Intron 1 of 22	ENST00000230124.8	NP_055660.1	Q92562
FIG4	XM_011536281.4 link	c.4-7T>C		splice_region_variant, intron_variant	Intron 1 of 22		XP_011534583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FIG4	ENST00000230124.8 link	c.67-7T>C		splice_region_variant, intron_variant	Intron 1 of 22	1	NM_014845.6	ENSP00000230124.4		Q92562

Frequencies

GnomAD3 genomes

AF:

0.0425

AC:

6471

AN:

152178

Hom.:

174

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0190

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0728

Gnomad ASJ

AF:

0.0634

Gnomad EAS

AF:

0.0157

Gnomad SAS

AF:

0.0863

Gnomad FIN

AF:

0.0267

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0505

Gnomad OTH

AF:

0.0441

GnomAD2 exomes

AF:

0.0590

AC:

14749

AN:

250030

AF XY:

0.0592

show subpopulations

Gnomad AFR exome

AF:

0.0183

Gnomad AMR exome

AF:

0.121

Gnomad ASJ exome

AF:

0.0607

Gnomad EAS exome

AF:

0.00849

Gnomad FIN exome

AF:

0.0315

Gnomad NFE exome

AF:

0.0530

Gnomad OTH exome

AF:

0.0564

GnomAD4 exome

AF:

0.0538

AC:

72614

AN:

1349290

Hom.:

2245

Cov.:

AF XY:

0.0545

AC XY:

36943

AN XY:

677842

show subpopulations

African (AFR)

AF:

0.0155

AC:

488

AN:

31402

American (AMR)

AF:

0.115

AC:

5126

AN:

44504

Ashkenazi Jewish (ASJ)

AF:

0.0645

AC:

1635

AN:

25356

East Asian (EAS)

AF:

0.0198

AC:

773

AN:

39078

South Asian (SAS)

AF:

0.0796

AC:

6674

AN:

83832

European-Finnish (FIN)

AF:

0.0335

AC:

1775

AN:

52950

Middle Eastern (MID)

AF:

0.0287

AC:

156

AN:

5430

European-Non Finnish (NFE)

AF:

0.0527

AC:

53201

AN:

1010248

Other (OTH)

AF:

0.0493

AC:

2786

AN:

56490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

3182

6364

9545

12727

15909

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1958

3916

5874

7832

9790

<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:

0.0426

AC:

6486

AN:

152296

Hom.:

175

Cov.:

AF XY:

0.0421

AC XY:

3134

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0190

AC:

788

AN:

41568

American (AMR)

AF:

0.0731

AC:

1118

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0634

AC:

220

AN:

3472

East Asian (EAS)

AF:

0.0160

AC:

AN:

5196

South Asian (SAS)

AF:

0.0861

AC:

415

AN:

4818

European-Finnish (FIN)

AF:

0.0267

AC:

283

AN:

10616

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0505

AC:

3436

AN:

68016

Other (OTH)

AF:

0.0474

AC:

100

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

310

620

930

1240

1550

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0469

Hom.:

Bravo

AF:

0.0458

Asia WGS

AF:

0.0570

AC:

199

AN:

3474

EpiCase

AF:

0.0526

EpiControl

AF:

0.0517

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 24, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 22, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Amyotrophic lateral sclerosis type 11

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease type 4J

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Charcot-Marie-Tooth disease type 4

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

0.41

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00050

dbscSNV1_RF

Benign

0.0

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over