6-109732621-GTTT-GTTTT

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBA1

The NM_014845.6(FIG4):c.447-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.80 ( 46681 hom., cov: 0)

Exomes 𝑓: 0.50 ( 24987 hom. )

Failed GnomAD Quality Control

Consequence

FIG4
NM_014845.6 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:12

Conservation

PhyloP100: -0.0950

Publications

4 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 -14 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.018722467 fraction of the gene. Cryptic splice site detected, with MaxEntScore 13, offset of 0 (no position change), new splice context is: tttgttttttttttttttAGgta. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BP6

Variant 6-109732621-G-GT is Benign according to our data. Variant chr6-109732621-G-GT is described in ClinVar as Benign. ClinVar VariationId is 694980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.9 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FIG4	NM_014845.6 link	c.447-3dupT		splice_acceptor_variant, intron_variant	Intron 4 of 22	ENST00000230124.8	NP_055660.1	Q92562
FIG4	XM_011536281.4 link	c.384-3dupT		splice_acceptor_variant, intron_variant	Intron 4 of 22		XP_011534583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FIG4	ENST00000230124.8 link	c.447-16_447-15insT		intron_variant	Intron 4 of 22	1	NM_014845.6	ENSP00000230124.4		Q92562

Frequencies

GnomAD3 genomes

AF:

0.795

AC:

117100

AN:

147288

Hom.:

46661

Cov.:

show subpopulations

Gnomad AFR

AF:

0.908

Gnomad AMI

AF:

0.704

Gnomad AMR

AF:

0.761

Gnomad ASJ

AF:

0.775

Gnomad EAS

AF:

0.691

Gnomad SAS

AF:

0.683

Gnomad FIN

AF:

0.759

Gnomad MID

AF:

0.750

Gnomad NFE

AF:

0.758

Gnomad OTH

AF:

0.780

GnomAD2 exomes

AF:

0.557

AC:

91581

AN:

164298

AF XY:

0.554

show subpopulations

Gnomad AFR exome

AF:

0.643

Gnomad AMR exome

AF:

0.523

Gnomad ASJ exome

AF:

0.524

Gnomad EAS exome

AF:

0.541

Gnomad FIN exome

AF:

0.602

Gnomad NFE exome

AF:

0.567

Gnomad OTH exome

AF:

0.536

GnomAD4 exome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.504

AC:

430169

AN:

853140

Hom.:

24987

Cov.:

AF XY:

0.505

AC XY:

223209

AN XY:

442374

show subpopulations

African (AFR)

AF:

0.540

AC:

10719

AN:

19864

American (AMR)

AF:

0.498

AC:

18460

AN:

37060

Ashkenazi Jewish (ASJ)

AF:

0.504

AC:

10175

AN:

20208

East Asian (EAS)

AF:

0.509

AC:

16719

AN:

32832

South Asian (SAS)

AF:

0.496

AC:

33087

AN:

66744

European-Finnish (FIN)

AF:

0.523

AC:

18419

AN:

35222

Middle Eastern (MID)

AF:

0.547

AC:

2293

AN:

4190

European-Non Finnish (NFE)

AF:

0.503

AC:

300774

AN:

598224

Other (OTH)

AF:

0.503

AC:

19523

AN:

38796

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

10429

20858

31288

41717

52146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8298

16596

24894

33192

41490

<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:

0.795

AC:

117151

AN:

147336

Hom.:

46681

Cov.:

AF XY:

0.792

AC XY:

56665

AN XY:

71576

show subpopulations

African (AFR)

AF:

0.908

AC:

36607

AN:

40318

American (AMR)

AF:

0.761

AC:

11244

AN:

14772

Ashkenazi Jewish (ASJ)

AF:

0.775

AC:

2667

AN:

3440

East Asian (EAS)

AF:

0.692

AC:

3489

AN:

5044

South Asian (SAS)

AF:

0.683

AC:

3197

AN:

4684

European-Finnish (FIN)

AF:

0.759

AC:

6916

AN:

9108

Middle Eastern (MID)

AF:

0.740

AC:

213

AN:

288

European-Non Finnish (NFE)

AF:

0.758

AC:

50603

AN:

66754

Other (OTH)

AF:

0.780

AC:

1579

AN:

2024

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1133

2266

3398

4531

5664

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

850

1700

2550

3400

4250

<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:

0.556

Hom.:

1380

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

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

- -

Charcot-Marie-Tooth disease

Uncertain:1Benign:1

Aug 14, 2019

Genesis Genome Database

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bilateral parasagittal parieto-occipital polymicrogyria

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Yunis-Varon syndrome

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Amyotrophic lateral sclerosis type 11

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease type 4J

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Aug 27, 2018

GeneDx

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

PhyloP100

-0.095

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over