rs56378532

Positions:

chr6-109715071-T-C

Variant summary

Our verdict is Benign. Variant got -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

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:

FIG4 (HGNC:):

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=-0.37).

BP6

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

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/exons	MANE	Protein	UniProt
FIG4	NM_014845.6 linkuse as main transcript	c.67-7T>C		splice_region_variant, intron_variant		ENST00000230124.8	NP_055660.1	Q92562
FIG4	XM_011536281.4 linkuse as main transcript	c.4-7T>C		splice_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.67-7T>C		splice_region_variant, intron_variant		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

GnomAD3 exomes

AF:

0.0590

AC:

14749

AN:

250030

Hom.:

609

AF XY:

0.0592

AC XY:

8006

AN XY:

135306

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 SAS exome

AF:

0.0822

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

Gnomad4 AFR exome

AF:

0.0155

Gnomad4 AMR exome

AF:

0.115

Gnomad4 ASJ exome

AF:

0.0645

Gnomad4 EAS exome

AF:

0.0198

Gnomad4 SAS exome

AF:

0.0796

Gnomad4 FIN exome

AF:

0.0335

Gnomad4 NFE exome

AF:

0.0527

Gnomad4 OTH exome

AF:

0.0493

GnomAD4 genome

AF:

0.0426

AC:

6486

AN:

152296

Hom.:

175

Cov.:

AF XY:

0.0421

AC XY:

3134

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0190

Gnomad4 AMR

AF:

0.0731

Gnomad4 ASJ

AF:

0.0634

Gnomad4 EAS

AF:

0.0160

Gnomad4 SAS

AF:

0.0861

Gnomad4 FIN

AF:

0.0267

Gnomad4 NFE

AF:

0.0505

Gnomad4 OTH

AF:

0.0474

Alfa

AF:

0.0472

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 22, 2021	- -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Amyotrophic lateral sclerosis type 11

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

-0.37

CADD

Benign

DANN

Benign

0.90

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

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