rs10499054

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_014845.6(FIG4):c.1948+3A>G variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.598 in 1,518,784 control chromosomes in the GnomAD database, including 287,180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 21481 hom., cov: 32)

Exomes 𝑓: 0.61 ( 265699 hom. )

Consequence

FIG4
NM_014845.6 splice_donor_region, intron

Scores

Splicing: ADA: 0.04755

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 4.54

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 6-109785031-A-G is Benign according to our data. Variant chr6-109785031-A-G is described in ClinVar as [Benign]. Clinvar id is 260447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-109785031-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FIG4	NM_014845.6 linkuse as main transcript	c.1948+3A>G		splice_donor_region_variant, intron_variant		ENST00000230124.8	NP_055660.1
FIG4	XM_011536281.4 linkuse as main transcript	c.1885+3A>G		splice_donor_region_variant, intron_variant			XP_011534583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FIG4	ENST00000230124.8 linkuse as main transcript	c.1948+3A>G		splice_donor_region_variant, intron_variant		1	NM_014845.6	ENSP00000230124	P4

Frequencies

GnomAD3 genomes

AF:

0.490

AC:

74492

AN:

151876

Hom.:

21490

Cov.:

show subpopulations

Gnomad AFR

AF:

0.196

Gnomad AMI

AF:

0.631

Gnomad AMR

AF:

0.508

Gnomad ASJ

AF:

0.569

Gnomad EAS

AF:

0.327

Gnomad SAS

AF:

0.348

Gnomad FIN

AF:

0.543

Gnomad MID

AF:

0.497

Gnomad NFE

AF:

0.674

Gnomad OTH

AF:

0.520

GnomAD3 exomes

AF:

0.528

AC:

132285

AN:

250486

Hom.:

38211

AF XY:

0.533

AC XY:

72215

AN XY:

135394

show subpopulations

Gnomad AFR exome

AF:

0.188

Gnomad AMR exome

AF:

0.438

Gnomad ASJ exome

AF:

0.555

Gnomad EAS exome

AF:

0.332

Gnomad SAS exome

AF:

0.357

Gnomad FIN exome

AF:

0.556

Gnomad NFE exome

AF:

0.672

Gnomad OTH exome

AF:

0.573

GnomAD4 exome

AF:

0.610

AC:

833467

AN:

1366790

Hom.:

265699

Cov.:

AF XY:

0.604

AC XY:

414332

AN XY:

685482

show subpopulations

Gnomad4 AFR exome

AF:

0.173

Gnomad4 AMR exome

AF:

0.448

Gnomad4 ASJ exome

AF:

0.555

Gnomad4 EAS exome

AF:

0.318

Gnomad4 SAS exome

AF:

0.361

Gnomad4 FIN exome

AF:

0.567

Gnomad4 NFE exome

AF:

0.669

Gnomad4 OTH exome

AF:

0.566

GnomAD4 genome

AF:

0.490

AC:

74484

AN:

151994

Hom.:

21481

Cov.:

AF XY:

0.480

AC XY:

35659

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.195

Gnomad4 AMR

AF:

0.508

Gnomad4 ASJ

AF:

0.569

Gnomad4 EAS

AF:

0.327

Gnomad4 SAS

AF:

0.349

Gnomad4 FIN

AF:

0.543

Gnomad4 NFE

AF:

0.674

Gnomad4 OTH

AF:

0.516

Alfa

AF:

0.623

Hom.:

52268

Bravo

AF:

0.478

Asia WGS

AF:

0.313

AC:

1089

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 22, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Amyotrophic lateral sclerosis type 11

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Yunis-Varon syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Bilateral parasagittal parieto-occipital polymicrogyria

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Charcot-Marie-Tooth disease type 4J;C2675491:Amyotrophic lateral sclerosis type 11

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 28, 2017

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Charcot-Marie-Tooth disease type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.048

dbscSNV1_RF

Benign

0.14

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over